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British journal of clinical pharmacology : BJCP 88(12), 5149-5165 (2022). doi:10.1111/bcp.15467 special issue: "Themed Issue: Methodological Consideration in Research and Development of Medicines for Children (C4C / Issue Edited by: Ian Wong, Saskia Dewildt", Published by Wiley-Blackwell, Oxford

Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum.A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization.The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26-44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169).GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population.

Translational Psychiatry 11(1), 467 (2021). doi:10.1038/s41398-021-01591-5, Published by Nature Publishing Group, London

Background and aims The Hepatitis E virus hijacks the endosomal system for its release. These structures are highly dependent on cholesterol. Hence, this study investigates the impact of HEV on cholesterol-metabolism, the effect of intracellular cholesterol content on HEV-release and the potential of cholesterol-modulators to serve as antivirals. Methods Intracellular cholesterol-content of cells was modulated and impacts on HEV were monitored using qPCR, Western blot, microscopy, virus-titration and density-gradient centrifugation. Blood-lipids and HEV-RNA were routinely quantified in chronically infected patients during follow-up visits. Results In HEV-infected cells, decreased levels of cholesterol are found. In patients, HEV infection decreases serum-lipid concentrations. Importantly, statin treatment herein increases viral titers. Similarly, reduction of intracellular cholesterol via simvastatin treatment increases viral release in vitro. On the contrary, elevating intracellular cholesterol via LDL or 25-hydroxycholesterol strongly reduces viral release due to enhanced lysosomal degradation of HEV. Drug-induced elevation of intracellular cholesterol via fenofibrate or PSC833 impairs HEV release via the same mechanism. Conclusions This study analyses the crosstalk between HEV and intracellular cholesterol. The results highlight the importance of an intact cholesterol homeostasis for HEV-release and thereby identify a potential target for antiviral strategies. Especially fenofibrate is considered a promising novel antiviral against HEV. Beyond this, the study may help clinicians evaluating co-treatments of HEV-infected patients with statins, as this may be counter indicated., Graphical abstract

Contains fulltext : 238693.pdf (Publisher’s version ) (Open Access) Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

Aims Older patients in particular suffer from adverse drug reactions (ADR) when presenting in the emergency department. We aimed to characterise the phenotype of those ADRs, to be able to recognise an ADR in older patients. Methods Cases of ADRs in emergency departments collected within the multicentre prospective observational study (ADRED) were analysed (n = 2215). We analysed ADR‐associated diagnoses, symptoms and their risk profiles. We present frequencies and odds ratios (OR) with 95% confidence intervals for adults (18–64 years) compared to older adults (≥65 years; young–old 65–79, old–old ≥80 years) and regression coefficients (B) for each year of age. Results Most prominent differences were seen for drug‐associated confusion, dehydration, and bradycardia (OR 6.70 [1.59–28.27], B .054; OR 6.02 [2.41–15.03], B .081, and 4.82 [2.21–10.54], B .040), more likely seen in older adults. Bleedings were reported in all age groups, but gastrointestinal bleedings occurred with more than doubled chance in older adults (OR 2.46 [1.77–3.41], B .030), likewise did other bleedings such as haemorrhage from respiratory passages (OR 2.89 [1.37–6.11], B.036). Falls were more likely in older adults (OR 2.84 [1.77–4.53], B .030), while dizziness was frequent in both age groups. Conclusion Our data point to differences in symptoms of ADRs between adults and older individuals, with dangerous drug‐associated phenomena in the older adult such as bleedings or falls. Physicians should consider drug‐associated origins of symptoms in older adults with an increased risk for serious health problems., publishedVersion

Background For treatment with psychotropic drugs during pregnancy, extended therapeutic drug monitoring is recommended for individual therapy adjustment. We measured venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and active moiety, AM (sum of VEN+ODV) concentrations in maternal serum, amniotic fluid and umbilical cord blood. Methods Concentrations of VEN, ODVEN and AM were measured in nine mother-infant pairs at time of delivery; in five cases, amniotic fluid samples were available. Concentrations are reported as median values, first (Q1) and third (Q3) quartiles and ranges. Penetration ratio was calculated by dividing concentrations of VEN, ODVEN and AM in amniotic fluid and umbilical cord blood by maternal serum concentrations. Results Median daily dosage of venlafaxine was 75 mg (range 37.5–225 mg). There were no significant correlations between daily dose, maternal serum, umbilical cord blood and amniotic fluid concentrations. Median penetration ratio into amniotic fluid was 2.5 (range 0.56–4.48). Median penetration ratio into fetal circulation was 1.05 (range 0.62–2.08). Median concentration of AM was 223.8 ng/mL, range 33.9–338.0 ng/mL (maternal serum), 789.0 ng/mL, range 309-1052.5 ng/mL (amniotic fluid) and 291.0 ng/mL, range 21.1–448.4 ng/mL (cord blood). Discussion VEN, ODVEN and AM concentrations in maternal serum, amniotic fluid and umbilical cord blood indicate that the fetus might have been exposed to relatively high concentrations throughout pregnancy. High concentrations in amniotic fluid indicate an increased penetration into and/or accumulation within amniotic fluid and a decreased elimination out of amniotic fluid. Findings indicate that fetal in-utero exposition to venlafaxine is higher compared to other antidepressants.

Ingmar Bergs,1 Katja S Just,2 Annegret Müller,1 Julia C Stingl,2,&ast; Michael Dreher1,&ast; 1Department of Pneumology and Internal Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany; 2Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, Germany&ast;These authors contributed equally to this workCorrespondence: Ingmar Bergs, Department of Pneumology and Internal Intensive Care Medicine, University Hospital RWTH Aachen, Pauwelsstr. 30, Aachen, 52074, Germany, Tel +49 241/80 35443, Email ibergs@ukaachen.dePurpose: Dyspnea is a leading symptom of COPD that causes presentations in emergency departments or negatively impacts on them. Guideline-based inhalation therapies are intended to reduce dyspnea in COPD patients. This study analyzed how common guideline recommended inhalation therapy regimens are occurring in clinical practice among COPD patients presenting to emergency departments due to adverse drug reactions in polytherapy using data of the German ADRED database.Patients and Methods: In total, 269 COPD cases were identified. In a further analysis, all cases were analyzed for documented GOLD stage and guideline-recommended inhalation therapy for COPD. Dyspnea and other symptoms identified during ED presentation were analyzed and compared between patients who did and did not receive the guideline’s recommended inhalation therapy.Results: In this observation, 41% (n = 46) of all 112 cases with a documented COPD and GOLD stage received an underdosed therapy according to current guidelines. Dyspnea was the most common identified symptom (32%, n = 36) in this cohort and occurred more often in patients who received an underdosage of inhalation therapy (p < 0.01).Conclusion: Patients with COPD presenting to ED with ADRs show a high rate of non-guideline-recommended inhalation therapy and present more often with dyspnea compared to those COPD patients who received an adequate dosing of inhalation therapy.Keywords: emergency department, dyspnea, guideline therapy, chronic obstructive pulmonary disease, adverse drug events

Basic & clinical pharmacology & toxicology : BCPT 130(1), 132-140 (2022). doi:10.1111/bcpt.13681, Published by Wiley-Blackwell, Oxford

British journal of clinical pharmacology : BJCP 88(5), 2380-2395 (2022). doi:10.1111/bcp.15175, Published by Wiley-Blackwell, Oxford

Introduction The prevalence of psychotropic drug use in our society is increasing especially in older adults, thereby provoking severe adverse drug reactions (ADR). To identify specific patient risk profiles associated with psychotropic drug use in the situation of polymedication. Methods Cases of ADRs in general emergency departments (ED) collected within the multi-center prospective observational study (ADRED) were analyzed (n=2215). We compared cases with use of psychotropic drugs and without concerning their clinical presentation at the ED. Results A third of patients (n=731, 33%) presenting to the ED with an ADR took at least 1 psychotropic drug. Patients with psychotropic drug use tended to be older, more often female, and took a higher number of drugs (all p Discussion The association of psychotropic drug use with fall and syncope in combination with polymedication and older age leads to the suspicion that psychotropic drugs might be potentially harmful in specific risk populations such as older adults. It may lead us to thoroughly weigh the benefit against risk in a patient-oriented way, leading to an integrative personalized therapy approach.

PLOS ONE 16(3), e0247446 (2021). doi:10.1371/journal.pone.0247446, Published by PLOS, San Francisco, California, US

Hypoglycemia is a potentially life-threatening drug event under antidiabetic treatment. The aim of the study was to examine time trends in severe hypoglycemia in older adults with type 2 diabetes mellitus (T2DM) and antidiabetic treatment.Multicenter prospective diabetes patient follow-up registry (DPV).Patients aged ≥75 years with T2DM and documented treatment between 2005 and 2019.Outcomes of interest were rates of severe hypoglycemia, diabetes therapy, body mass index, HbA1c, and estimated glomerular filtration rate. Time trends of outcomes were analyzed in the whole cohort and compared between age groups (75-80, 80-85, ≥85 years).A total of 136,931 patients from 188 diabetes centers were included. The adjusted HbA1c decreased from 7.3% (95% confidence interval 7.3-7.4) in 2005 to 7.2% (7.2-7.2) in 2019 (P.001), with no significant difference between age groups (P = .47). Rates of severe hypoglycemia decreased from 6.7 (6.0-7.4) to 4.1 of 100 person-years (3.7-4.5) (P.001) in the entire population. Patients aged ≥85 years had constantly lower HbA1c levels compared with younger groups (P.001). Although severe hypoglycemia decreased the most in the ≥85 age group (P.001), severe hypoglycemia remained consistently higher in this group compared with the 75 to80 years group (P.001).During the analyzed time, the risk for severe hypoglycemia decreased. Although drugs with intrinsic risk for hypoglycemia were used less frequently, antidiabetic treatment in older adults should be further improved to continue reducing severe hypoglycemia in this age group, potentially accepting less strict metabolic control and age-specific target ranges.

Objectives ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. Methods The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. Results The genotype distribution met the Hardy–Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p Conclusions This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.

BMC pharmacology & toxicology 22(1), 56 (2021). doi:10.1186/s40360-021-00520-y, Published by BioMed Central, London

Allergy : European journal of allergy and clinical immunology 77(7), 2080-2089 (2022). doi:10.1111/all.15189, Published by Wiley, Oxford

We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R‐ and S‐PZQ in healthy male participants. This was toward evaluating the risk of drug‐drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non‐randomized, open‐label, single‐dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC‐MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T 1/2, C min, and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p, The effect of efavirenz and ritonavir on the pharmacokinetics of praziquantel (PZQ) were investigated. An open label, single dose one sequence crossover clinical study with 26 healthy male volunteers was conducted. Efavirenz decreased the AUC of PZQ 4‐fold (p

Therapeutic innovation & regulatory science: official journal of DIA 56(2), 244-254 (2022). doi:10.1007/s43441-021-00352-2, Published by Springer Nature, [New York]

British journal of clinical pharmacology : BJCP 87(7), 2732-2756 (2021). doi:10.1111/bcp.14671, Published by Wiley-Blackwell, Oxford

Objective Data regarding the ability of antidepressants to enter fetal, newborn and infant fluids have become gradually available, but mechanisms of antidepressant transfer remain poorly understood. Here we calculated penetration ratios in an array of matrices from combined samples of pregnant/breastfeeding women taking antidepressants. Method We performed a systematic literature search of PubMed and EMBASE to identify studies with concentrations of antidepressants from maternal blood, amniotic fluid, umbilical cord blood and/or breast milk. Penetration ratios were calculated by dividing the concentrations in amniotic fluid, umbilical cord plasma or breast milk by the maternal plasma concentration. When data from multiple studies were available, we calculated combined penetration ratios, weighting the study mean by study size. Results Eighty-five eligible studies were identified. For amniotic fluid, the highest penetration ratios were estimated for venlafaxine (mean 2.77, range 0.43-4.70 for the active moiety) and citalopram (mean 2.03, range 0.35-6.97), while the lowest ratios were for fluvoxamine (mean 0.10) and fluoxetine (mean 0.11, range 0.02-0.20 for the active moiety). For umbilical cord plasma, nortriptyline had the highest ratio (mean 2.97, range 0.25-26.43) followed by bupropion (mean 1.14, range 0.3-5.08). For breast milk, the highest ratios were observed for venlafaxine (mean 2.59, range 0.85-4.85), mianserin (mean 2.22, range 0.80-3.64) and escitalopram (mean 2.19, range 1.68-3.00). Conclusion We observed considerable variability across antidepressants regarding their ability to enter fetal, newborn and infant fluids. Measuring antidepressant concentrations in a maternal blood sample can provide a reliable estimate of fetal/infant exposure, although further evidence for concentration-dependent effects is required.

Antidepressant therapy is still associated with delays in symptomatic improvement and low response rates. Incomplete understanding of molecular mechanisms underlying antidepressant effects hampered the identification of objective biomarkers for antidepressant response. In this work, we studied transcriptome-wide expression followed by pathway analysis in lymphoblastoid cell lines (LCLs) derived from 17 patients documented for response to SSRI antidepressants from the Munich Antidepressant Response Signatures (MARS) study upon short-term incubation (24 and 48 h) with citalopram. Candidate transcripts were further validated with qPCR in MARS LCLs from responders (n = 33) vs. non-responders (n = 36) and afterward in an independent cohort of treatment-resistant patients (n = 20) vs. first-line responders (n = 24) from the STAR*D study. In MARS cohort we observed significant associations of GAD1 (glutamate decarboxylase 1; p = 0.045), TBC1D9 (TBC1 Domain Family Member 9; p = 0.014–0.021) and NFIB (nuclear factor I B; p = 0.015–0.025) expression with response status, remission status and improvement in depression scale, respectively. Pathway analysis of citalopram-altered gene expression indicated response-status-dependent transcriptional reactions. Whereas in clinical responders neural function pathways were primarily up- or downregulated after incubation with citalopram, deregulated pathways in non-responders LCLs mainly involved cell adhesion and immune response. Results from the STAR*D study showed a marginal association of treatment-resistant depression with NFIB (p = 0.068) but not with GAD1 (p = 0.23) and TBC1D9 (p = 0.27). Our results propose the existence of distinct pathway regulation mechanisms in responders vs. non-responders and suggest GAD1, TBC1D9, and NFIB as tentative predictors for clinical response, full remission, and improvement in depression scale, respectively, with only a weak overlap in predictors of different therapy outcome phenotypes.

Pharmacoepidemiology and drug safety 28(3), 377-388 (2019). doi:10.1002/pds.4726, Published by Wiley, Chichester [u.a.]

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors. While changes in reward expectations activated ventral striatal areas as in previous studies, mean reward rates preferentially modulated the substantia nigra/ventral tegmental area, deep layers of the superior colliculi, and a posterior pontomesencephalic region. These brainstem structures may work together to set motivation and attentional efforts levels according to perceived reward opportunities.

The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients' ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. The analysis of the TP53 and PPM1D genes, both intimately involved in chemotherapy-induced and/or age-related clonal hematopoiesis (CH), in 523 patients and 1,053 age-matched female control individuals revealed that CH represents a frequent event following chemotherapy, affecting 26 of the 523 patients enrolled (5.0%). Considering that TP53 mutations may arise from chemotherapy-induced CH, our findings help to avoid false-positive genetic diagnoses of LFS1.

Introduction Drug–drug interactions (DDIs) are an important risk factor for adverse drug reactions. Older, polymedicated patients are particularly affected. Although antithrombotics have been detected as high-risk drugs for DDIs, data on older patients exposed to them are scarce. Methods Baseline data of 365 IDrug study outpatients (≥ 60 years, use of an antithrombotic and one or more additional long-term drug) were analyzed regarding potential drug–drug interactions (pDDIs) with a clinical decision support system. Data included prescription and self-medication drugs. Results The prevalence of having one or more pDDI was 85.2%. The median number of alerts per patient was three (range 0–17). For 58.4% of the patients, potential severe/contraindicated interactions were detected. Antiplatelets and non-steroidal anti-inflammatory drugs (NSAIDs) showed the highest number of average pDDI alert involvements per use (2.9 and 2.2, respectively). For NSAIDs, also the highest average number of severe/contraindicated alert involvements per use (1.2) was observed. 91.8% of all pDDI involvements concerned the 25 most frequently used drug classes. 97.5% of the severe/contraindicated pDDIs were attributed to only nine different potential clinical manifestations. The most common management recommendation for severe/contraindicated pDDIs was to intensify monitoring. Number of drugs was the only detected factor significantly associated with increased number of pDDIs (p

Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions.Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated.This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine.The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Objectives Many studies describing an association of drugs with falls focus mostly on drugs acting in the central nervous system. We aim to analyze the association of all drugs taken with falls in older adults. Design Prospective population-based study (ActiFE study). Setting and Participants A total of 1377 community-dwelling older adults with complete recording of falls and baseline information on drug intake. Methods Negative binomial regression was used to analyze the association of 34 drug classes with a 12-month incidence rate ratio (IRR) of falls adjusting for age, sex, comorbidities, gait speed, balance, chair rise, kidney function, liver disease, and smoking. Results Participants took a median 3 drugs (interquartile range 1, 5), with 34.5% (n = 469) having ≥5 drugs. The median IRR for a fall per person-year was overall 0.72 [95% confidence interval (CI) 0.60–0.83] and 2.22 (95% CI 1.90–2.53) among those who experienced ≥1 fall. The following drug classes showed significant associations: antiparkinsonian medication [IRR 2.68 (95% CI 1.59–4.51)], thyroid therapy [IRR 1.40 (95% CI 1.08–1.81)], and systemic corticosteroids [IRR 0.33 (95% CI 0.13–0.81)]. Among fall-risk-increasing drugs only antiepileptics [IRR 2.16 (95% CI 1.10–4.24)] and urologicals [IRR 2.47 (95% CI 1.33–4.59)] were associated with falls in those participants without a prior fall history at baseline. Conclusion and Implications Additional drug classes, such as antiparkinsonian medication, thyroid therapy, and systemic corticosteroids, might be associated with falls in older adults, possibly representing pharmacological effects on the musculoskeletal and central nervous systems. Further evaluations in larger study populations are recommended.

Falls is a frequent type of adverse drug reactions causing significant morbidity and mortality in the elderly. We reviewed, with which drugs the risk of falls is relevant and might depend on genomic variation. Pharmacogenetic variability may contribute to drug-induced falls for instance mediated by impaired drug elimination due to inherited deficiency in enzymes like CYP2C9, CYP2C19 and CYP2D6. The relative role of specific genes and polymorphisms in old age may differ from younger people. Biomarkers for frailty, but also genomic biomarkers might help identifying patients at high risk for drug-induced falls. Many other factors including disease and drug–drug interactions also contribute to risk of falls. Further studies analyzing the impact of genomic variation on the medication-related fall risk in the older adult are urgently needed.

The MR signal from gray matter has been long known to present small differences in intensity that have been attributed to variations in cortical myelin content. Previous studies have shown that the T1-, T2-weighted signal and their ratio are sensitive to these variations. Here, we investigated different combinations of signal from MPRAGE and FLAIR images in multimodal segmentation with parametric models of signal intensity to identify a procedure for the identification of contrast in cortical gray matter and the segmentation of different cortical components at 3T. We show that a three-modal combination of these signals delivers a stable segmentation of the cortical mantle in which two distinct components are reliably identified. The resulting intensity maps correspond well to known regional myeloarchitectural differences between cortical regions. These results confirm that widely available MR sequences contain signal that may be used to reliably detect subtle differences in the composition of gray matter with a segmentation approach.

The present functional neuroimaging study focuses on the iconography of mourning. A culture-specific pattern of body postures of mourning individuals, mostly suggesting withdrawal, emerged from a survey of visual material. When used in different combinations in stylized drawings in our neuroimaging study, this material activated cortical areas commonly seen in studies of social cognition (temporo-parietal junction, superior temporal gyrus, and inferior temporal lobe), empathy for pain (somatosensory cortex), and loss (precuneus, middle/posterior cingular gyrus). This pattern of activation developed over time. While in the early phases of exposure lower association areas, such as the extrastriate body area, were active, in the late phases activation in parietal and temporal association areas and the prefrontal cortex was more prominent. These findings are consistent with the conventional and contextual character of iconographic material, and further differentiate it from emotionally negatively valenced and high-arousing stimuli. In future studies, this neuroimaging assay may be useful in characterizing interpretive appraisal of material of negative emotional valence.

Viruses 12(11), 1219 (2020). doi:10.3390/v12111219, Published by MDPI, Basel

Introduction: Pregnancy-related physiological changes exert a crucial impact on the pharmacokinetics of antidepressants; however, the current evidence presents inconsistencies. A clearer understanding of pregnancy-related effects on antidepressant disposition may facilitate the development of guidelines for appropriate dose adjustments during the course of pregnancy based on therapeutic drug monitoring. Areas covered: We systematically reviewed studies comparing antidepressant levels in the same individuals during pregnant and non-pregnant states. Using dose-adjusted plasma concentration measurements, we estimated alteration ratios between the 3rd trimester and baseline (before or after pregnancy). Additionally, we performed a meta-analysis for changes in dose-adjusted concentrations to estimate mean differences. Expert opinion: Data for several antidepressants display clear alteration patterns during pregnancy. On the basis of the alteration ratios trimipramine, fluvoxamine, and nortriptyline show a prominent decrease in dose-adjusted levels, especially in the 3rd trimester. Clomipramine, imipramine, citalopram, and paroxetine show smaller decreases in dose-adjusted concentrations in the third trimester. For escitalopram, venlafaxine and fluoxetine, changes are considered negligible. For sertraline, there was a tendency toward increased dose-adjusted concentrations in pregnancy. Available evidence suffers from major limitations and factors affecting pharmacokinetics have been insufficiently addressed. Further research is required to promote knowledge on pregnancy effects on antidepressant pharmacokinetics.

IntroductionPre-emptive testing of pharmacogenetically relevant single-nucleotide polymorphisms can be an effective tool in the prevention of adverse drug reactions and therapy resistance. However, most of the tests are not used as standard in routine care in Germany because of lacking evidence for the clinical and economical benefit and their impact on the usage of healthcare services. We address this issue by investigating the influence of pharmacogenetic profiles on the use of healthcare services over an extended period of several years using routine care data from a statutory health insurance company. The goal is to provide clinical evidence whether pre-emptive pharmacogenetic testing of metabolic profiles in routine care in Germany is beneficial and cost-effective.Methods and analysisThe EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung) study is a non-interventional cohort study conducted to analyse pharmacogenetic risk factors that are important for drug therapy by means of endpoints relevant for healthcare. The analysis is based on pharmacogenetic profiles and statutory health insurance data. We perform pharmacogenetic, pharmacoepidemiological and pharmacoeconomic analyses using health care utilisation scores and machine learning techniques. Therefore, we aim to include about 10 000 patients (≥18 years) insured by the health insurance provider Techniker Krankenkasse. The study focuses on patients with prescriptions of anticoagulants and prescriptions of cholesterol-lowering drugs. Also, a screening for special pharmacogenetic characteristics will be performed in patients with at least one Y57.9! diagnosis (Complication of medical and surgical care: drug or medicament, unspecified). Outcomes include the utilisation of health insurance services, the incidence of incapacity for work and costs for drugs and treatment.Ethics and disseminationThe protocol was approved by the Ethics Committee of the Medical Faculty, University of Bonn (Lfd. Nr. 339/17). The results of this research project will be published in scientific open access journals and at conferences.Trial registration numberGerman Clinical Trials Register, DRKS00013909.

Background Older adults are more prone to develop adverse drug reactions (ADRs) since they exhibit numerous risk factors. The first aim was to analyse the number of spontaneous ADR reports regarding older adults (> 65) in the ADR database of the German Federal Institute for Drugs and Medical Devices (BfArM) and to set them in relation to i) the number of ADR reports concerning younger adults (19–65), and ii) the number of inhabitants and assumed drug-exposed inhabitants. The second aim was to analyse, if reported characteristics occurred more often in older vs. younger adults. Methods All spontaneous ADR reports involving older or younger adults within the period 01/01/2000–10/31/2017 were identified in the ADR database. Ratios concerning the number of ADR reports/number of inhabitants and ADR reports/drug-exposed inhabitants were calculated. The reports for older (n = 69,914) and younger adults (n = 111,463) were compared using descriptive and inferential statistics. Results The absolute number of ADR reports involving older adults increased from 1615 (2000) up to 5367 ADR reports (2016). The age groups 76–84 and 70–79 had the highest number of ADR reports with 25 ADR reports per 100,000 inhabitants and 27 ADR reports per 100,000 assumed drug-exposed inhabitants. For both ratios, the number of reports was higher for males (26 and 28 ADR reports) than for females (24 and 26 ADR reports). Fatal outcome was reported almost three times more often in older vs. younger adults. Six out of ten drug substances most frequently suspected were antithrombotics (vs. 1/10 in younger adults). For some drug substances (e.g. rivaroxaban) the ADRs reported most frequently differed between older (epistaxis) and younger adults (menorrhagia). Conclusions There is a need to further investigate ADRs in older adults since they occurred more frequently in older vs. younger adults and will likely increase in future. Physicians should be aware of different ADRs being attributed to the same drug substances which may be more prominent in older adults. Regular monitoring of older adults taking antithrombotics is recommended.

Clinical pharmacology & therapeutics : CPT 106(2), 313-316 (2019). doi:10.1002/cpt.1471 special issue: "Pharmacogenetics Pharmacogenomics", Published by Wiley-Blackwell, Hoboken, NJ

Adverse drug reactions (ADR) account for 5 to 7% of emergency department (ED) consultations. We aimed to assess medication risk profiles for ADRs leading to ED visits. We analysed medication intake and patient demographics in a prospective multi-centre observational study collecting ADR cases in four large EDs in Germany. Odds ratios (OR) were calculated to relate drug classes taken to those suspicious for an ADR after a causality assessment. A total of 2215 cases of ED visits due to ADRs were collected. The median age of the cohort was 73 years; in median, six co-morbidities and an intake of seven drugs were documented. Antineoplastic/immunomodulating agents had the highest OR for being suspected for an ADR (OR 20.45, 95% CI 14.54–28.77), followed by antithrombotics (OR 2.94, 95% CI 2.49–3.47), antibiotics (OR 2.65, 95% CI 1.78–3.95), systemic glucocorticoids (OR 2.43, 95% CI 1.54–3.82) and drugs affecting the central nervous system (CNS), such as antipsychotics (OR 2.36, 95% CI 1.46–3.81), antidepressants (OR 2.10, 95% CI 1.57–2.83), antiparkinsonian medication (OR 2.11, 95% CI 1.15–3.84), opioids (OR 1.79, 95% CI 1.26–2.54) and non-opioid analgesics (OR 1.32, 95% CI 1.01–1.72). Patients experiencing ADRs leading to ED visits are commonly old, multi-morbid and multi-medicated. CNS drugs may be more relevant than prior expected. With calculating ORs, we could replicate involvement of antineoplastic agents, antithrombotics, antibiotics, systemic glucocorticoids and non-opioid analgesics as frequently suspected for ADRs in EDs. DRKS-ID: DRKS00008979.

The cytochrome P450 enzyme 2D6 is involved in the metabolism of 20% of all commonly used drugs, including many psychotropic drugs and CNS-active substances. CYP2D6 is among the CYP enzymes with the highest expression levels in the brain, suggesting a role in the local brain metabolism of psychotropic drugs and the existence of endogenous substrates. The genetic polymorphism of CYP2D6, which causes individual differences in activity levels of the enzyme, has also been characterized functionally in human brain imaging studies. Here we explore the feasibility of predicting CYP2D6 phenotype using component-wise gradient boosting on fMRI resting brain perfusion images. The images belonged to subjects showing a range of genetic CYP2D6 variants. We achieved sensitivity and specificity values between 85% and 87% for the classification of ultrarapid metabolisers, and between 71% and 79% for poor metabolisers. An extension of the boosting algorithm, developed to improve the clinical plausibility of the inherently sparse models, produced enhanced models in agreement with the results of previous studies, showing some brain regions as positively associated with genotypic variation, most prominently in the prefrontal white matter and the corpus callosum. With further development, such a probabilistic method might constitute a valuable, non-invasive alternative to actual genotyping.

The goals of this German guideline are the improvement of diagnosis and therapy of scabies, the implementation of a coordinated action in outbreaks of scabies, and the control of this infestation in large migration or refugee flows.Sarcoptes scabiei var. hominis is transmitted by direct skin-to-skin contact of sufficient duration. The infectivity of female mites when removed from patients does not exceed 48 hours at room temperature (21°C) and relative humidity of 40-80%. The risk of infection rises proportionally to the number of mites on the skin and is particularly high in crusted scabies. As elderly persons tend to develop crusted scabies due to disease- or medication-related immunosuppression, there is an increased risk for outbreaks of scabies at nursing homes and extended-care facilities. The guideline contains detailed recommendations for management of such outbreaks. In refugees the prevalence of scabies is higher than in the general population in Germany, but the risk for outbreaks is not high. Scabies infestation should be considered when a recent onset of itching is associated with eczema and presence of burrows or comma-like papules at predilection sites. It is confirmed by dermatoscopic detection of mites or by microscopic identification of mites, mite eggs or fecal matter (scybala) from skin scrapings.The treatment of choice for common scabies is topical permethrin 5% cream applied for 8-12 hours. Permethrin can be considered for off-label use also in infants of less than 3 months of age and pregnant women. For this group crotamiton is another option, which, besides benzyl benzoate, presents a good second line therapy for the other indications. Indications for oral ivermectin, which has just been licensed in Germany, include patients with immunosuppression, severe dermatitis, and low adherence.Crusted scabies is preferentially treated by a combination of topical permethrin and oral ivermectin. Affected patients should be isolated, and all contact persons should be treated. The guideline contains lists for additional measures, including possible treatment of contact persons, clothes, linen and other possibly infested articles.

Aim The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. Methods From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. Results Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10 −4 ) and OS (p = 5.8 × 10 −5 ). Conclusion The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.

Highlights • Our study highlights the use of neuroimaging methods to detect and analyze therapy associated side effects, and the main finding of our study is that interferon, known to induce depression as adverse drug effect, leads to selective blunting of appetitive rather than affective stimuli. • Our study shows the utility of sophisticated imaging methods to assess and clarify the nature of subtle drug effects on emotional and cognitive behavior. • We think that the use of neuroimaging methods for the prediction and detection of off-target drug effects on mental health is an important topic in personalized medicine., Treatment with interferon (IFN) has been associated with depressive side effects. Previous neuroimaging studies have provided information about changes in brain activation patterns in patients under treatment with IFN-alpha, but the effect of other IFNs, or the role of the underlying disease, has yet to be clarified. In the present fMRI study, we looked at brain changes after 8 days of IFN-beta treatment in N = =17 healthy volunteers, thus avoiding the possible confound of the effects of underlying pathology in studies of IFN-treated patients with neurological or other medical disorders. We followed a symptom dimensional approach by simultaneously investigating two distinct symptom domains of depressiveness: negative affect (amygdala) and appetitive motivation (ventral striatum). In these early phases of IFN treatment we detected a selective change in neural substrates of appetitive motivation, consistent with the predominant symptomatic change recorded in psychopathology ratings. In contrast, the fMRI phenotype of negative affect, which is known to characterize disorders of affect involving anxiety and depressiveness as well as individual vulnerability to depression, was unchanged after treatment. These findings suggest that IFN may induce an affective syndrome through a mechanism involving down-regulation of appetitive motivation.

PLOS ONE 15(3), e0230632 (2020). doi:10.1371/journal.pone.0230632, Published by PLOS, San Francisco, California, US

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology.

Gastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects.The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in theWomen (These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.

The aim of this study was to measure and investigate correlations of lamotrigine concentrations in maternal as well as umbilical cord blood, amniotic fluid, and breast milk to account for the distribution of the drug. Concentrations of lamotrigine were measured in 19 mother–infant pairs at the time of delivery. To account for the penetration ratio into amniotic fluid, cord blood and breast milk, the concentration of lamotrigine in the particular environment was divided by the concentration in maternal serum. A no-intercept model was applied for associations between maternal serum concentrations, amniotic fluid, umbilical cord blood, and breast milk concentrations. The mean daily dosage of lamotrigine was 351.32 mg (range 50–650 mg). We detected associations between maternal serum and amniotic fluid (β = 0.088, p

Dementia and type 2 diabetes (T2D) are two major phenomena in older people. To compare anti-hyperglycemic therapy and diabetes-related comorbidities between elderly T2D patients with or without comorbid dementia.215,932 type 2 diabetes patients aged ≥ 40 years (median [Q1;Q3]: 70.4 [61.2;77.7] years) from the standardized, multicenter German/Austrian diabetes patient registry, DPV, were studied. To identify patients with comorbid dementia, the registry was searched by ICD-10 codes, DSM-IV/-5 codes, respective search terms and/or disease-specific medication. For group comparisons, multiple hierarchic regression modeling with adjustments for age, sex, and duration of diabetes was applied.3.1% (n=6770; 57% females) of the eligible T2D patients had clinically recognized comorbid dementia. After adjustment for demographics, severe hypoglycemia (insulin group: 14.8 ± 0.6 vs. 10.4 ± 0.2 events per 100 patient-years, p0.001), hypoglycemia with coma (insulin group: 7.6 ± 0.4 vs. 3.9 ± 0.1 events per 100 patient-years, p0.001), depression (9.9 vs. 4.7%, p0.001), hypertension (74.7 vs. 72.2%, p0.001), stroke (25.3 vs. 6.5%, p0.001), diabetic foot syndrome (6.0 vs. 5.2%, p=0.004), and microalbuminuria (34.7 vs. 32.2%, p0.001) were more common in dementia patients compared to T2D without dementia. Moreover, patients with dementia received insulin therapy more frequently (59.3 vs. 54.7%, p0.001), but metabolic control (7.7 ± 0.1 vs. 7.7 ± 0.1%) was comparable to T2D without dementia.In T2D with dementia, higher rates of hypoglycemia and other diabetes-related comorbidities were observed. Hence, the risks of a glucocentric and intense diabetes management with insulin and a focus on tight glycemic control without considering other factors may outweigh the benefits in elderly T2D patients with comorbid dementia.

Despite strong pharmacological support, association studies using genotype-predicted phenotype as a variable have yielded conflicting or inconclusive evidence to promote personalized pharmacotherapy. Unless the patient is a genotypic poor metabolizer, imputation of patient's metabolic capacity (or metabolic phenotype), a major factor in drug exposure-related clinical response, is a complex and highly challenging task because of limited number of alleles interrogated, population-specific differences in allele frequencies, allele-specific substrate-selectivity and importantly, phenoconversion mediated by co-medications and inflammatory co-morbidities that modulate the functional activity of drug metabolizing enzymes. Furthermore, metabolic phenotype and clinical outcomes are not binary functions; there is large intragenotypic and intraindividual variability. Therefore, the ability of association studies to identify relationships between genotype and clinical outcomes can be greatly enhanced by determining phenotype measures of study participants and/or by therapeutic drug monitoring to correlate drug concentrations with genotype and actual metabolic phenotype. To facilitate improved analysis and reporting of association studies, we propose acronyms with the prefixes ‘g’ (genotype-predicted phenotype) and ‘m’ (measured metabolic phenotype) to better describe this important variable of the study subjects. Inclusion of actually measured metabolic phenotype, and when appropriate therapeutic drug monitoring, promises to reveal relationships that may not be detected by using genotype alone as the variable.

Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual ( n=127) or according to a standardized algorithm ( n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01). Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment.