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Aims: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine., Methods: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations., Results: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q 1  = 15.5; Q 3  = 90.5 vs. 92.0 ng/mL, Q 1  = 52.3; Q 3  = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations., Conclusion: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: We aimed to investigate the ambiguous findings of earlier research regarding the reduction of quetiapine plasma levels when combined with lamotrigine, most likely via UDP-glucuronosyltransferase induction by lamotrigine., Methods: One thousand one hundred and fifty samples, divided into four groups of patients receiving either quetiapine immediate- (IR) or extended-release (XR) without or in combination with lamotrigine were compared regarding absolute and dose-adjusted plasma concentrations. Furthermore, samples of intra-individual controls were analyzed., Results: Patients receiving quetiapine IR in combination with lamotrigine showed 31% lower plasma ( p  = 0.002) and 23% lower dose-adjusted plasma concentrations ( p  = 0.004) compared to those receiving IR monotherapy. The proportion of patients with quetiapine plasma concentrations below the lower limit of the therapeutic reference range was 50% and 30% in the combination group and in patients receiving monotherapy, respectively ( p  = 0.03). However, no significant differences regarding plasma concentration ( p  = 0.13) and dose-adjusted plasma concentration ( p  = 0.42) were observed in patients with combination vs. monotherapy with the XR formulation of quetiapine. In the intra-individual controls, no trends could be identified, possibly due to insufficient number of samples ( p  > 0.05)., Conclusions: The combination of quetiapine IR with lamotrigine is associated with significantly lower drug concentrations of quetiapine, potentially impacting quetiapine effectiveness. For quetiapine ER, a significant interaction is less likely.

Background: To assess the pharmacokinetic correlates of reported adverse drug reactions (ADRs) under antidepressant treatment with escitalopram (ESC) using a large therapeutic drug monitoring database., Methods: A large naturalistic sample of inpatients and outpatients prescribed ESC was analyzed. ADRs were classified using the Udvalg for Kliniske Undersogelser side effect rating scale. We compared ESC-treated patients with (n = 35) and without ADRs (n = 273) using ESC plasma concentrations as the primary outcome. We also compared ADR rates in the 2 groups based on 2 cut-off ESC levels reflecting the recommended upper thresholds of the therapeutic reference range of 80 ng/mL, suggested by the consensus therapeutic drug monitoring guidelines, and 40 ng/mL, based on recent meta-analysis data. The effects of age, sex, smoking, daily ESC dose, plasma concentrations, and concentrations corrected for daily dose were included in a binary logistic regression model to predict ADRs., Results: No differences in clinical, demographic, or pharmacokinetic parameters were observed between patients with and without ADRs ( P > 0.05). Patients with ESC-related ADRs were more frequently diagnosed with psychotic disorders than those without (25% vs. 7.1%, P = 0.004). None of the variables was associated with ADR risk. Overall, ADR rates were not significantly different in patients above versus below thresholds of ESC concentrations (ESC concentrations >40 [n = 59] vs. ≤40 ng/mL [n = 249] and >80 [n = 8] vs. ≤80 ng/mL [n = 300]; P = 0.56 and P = 1.0, respectively)., Conclusions: No distinct pharmacokinetic patterns underlying ESC-associated ADRs were observed. Further studies with more specific assessments of ADRs in larger cohorts are required to better identify potential underlying patterns., Competing Interests: M. Kuzin has received travel grants from Sunovion Pharmaceutical (Basel, Switzerland) and Otsuka Pharmaceutical (Glattbrugg, Switzerland). He also received a travel grant, participated, and obtained a grant at speaker board of Lundbeck (Zurich, Switzerland). M. Paulzen has received speaker fees from the following pharmaceutical companies: Neurax Pharm, Lundbeck, Janssen, Otsuka, Idorsia, and Rovi. He has served as a consultant for Neurax Pharm, Otsuka, Lundbeck, Idorsia, and Rovi. He is an editor of PSIAC, an Internet-based drug–drug interaction program for psychopharmacotherapy ( www.psiac.de ). He reports no conflict of interest with this publication. Dr. Schoretsanitis has served as a consultant for Dexcel Pharma, HLS Therapeutics, and Thermo Fisher and has received speaker fees from HLS Therapeutics. The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Objective: We assessed pharmacokinetic correlates of treatment response to escitalopram using a large therapeutic drug monitoring database., Methods: A large naturalistic sample of patients receiving escitalopram was analyzed. Responders were defined as 'very much improved' or 'much improved' based on the Clinical Global Impression - Improvement score, CGI-I. We compared responders ( n  = 83) vs. non-responders ( n = 388) with the primary outcome being the escitalopram plasma concentration and concentration corrected by the daily dose (C/D ratio). Effects of age, sex, body-mass-index (BMI), and C/D ratio were assessed in a multivariate logistic regression model predicting response., Results: There were no statistically significant differences in clinical and demographic characteristics between responders vs. non-responders. There were also no differences between escitalopram daily doses or plasma concentrations, while C/D ratios were significantly higher in non-responders than in responders (1.6 ± 1.7 vs. 1.2 ± 0.9 (ng/mL)/(mg/day), p  = 0.007); C/D ratios (odds ratio 0.52, 95% confidence interval 0.34-0.80, p < 0.003) were associated with response to escitalopram, after controlling for age, sex, and BMI., Conclusions: Patients with low clearance of escitalopram as reflected upon high C/D ratios may be less likely respond to escitalopram. Identifying these patients during dose titration may support clinical decision-making, including switching to a different antidepressant instead of increasing daily dose.

Evidence regarding effectiveness and safety of clozapine once- vs. multiple-daily dosing is limited. We compared demographic and clinical parameters between patients with once- vs. multiple-daily dosing in the Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (AGATE dataset), and the Department of Psychiatry, Lausanne University Hospital, Switzerland, using non-parametric tests. Effectiveness and safety outcomes were available in the AGATE dataset. We performed a systematic review in PubMed/Embase until February 2022, meta-analyzing studies comparing clozapine once- vs. multiple-daily-dosing. We estimated a pooled odds ratio for adverse drug-induced reactions (ADRs) and meta-analyzed differences regarding clinical symptom severity, age, percentage males, smokers, clozapine dose, and co-medications between patients receiving once- vs. multiple-daily dosing. Study quality was assessed using the Newcastle-Ottawa-Scale. Of 1494 and 174 patients included in AGATE and Lausanne datasets, clozapine was prescribed multiple-daily in 74.8% and 67.8%, respectively. In the AGATE cohort, no differences were reported for the clinical symptoms severity or ADR rate (p > 0.05). Meta-analyzing eight cohorts with a total of 2810 clozapine-treated individuals, we found more severe clinical symptoms (p = 0.036), increased ADR risk (p = 0.01), higher clozapine doses (p < 0.001), more frequent co-medication with other antipsychotics (p < 0.001), benzodiazepines (p < 0.001), anticholinergics (p = 0.039), and laxatives (p < 0.001) in patients on multiple- vs. once-daily dosing. Of six studies, five were rated as good, and one as poor quality. Patients responding less well to clozapine may be prescribed higher doses multiple-daily, also treated with polypharmacy, potentially underlying worse safety outcomes. Patient preferences and adherence should be considered during regimen selection., (© 2022. The Author(s).)

Objective: We aimed to unravel potential pharmacokinetic interactions between aripiprazole and duloxetine., Methods: Plasma concentrations of aripiprazole in two groups of 78 patients each, receiving aripiprazole as a monotherapy or combined with duloxetine, were compared. A potential impact of duloxetine on the metabolism of aripiprazole was expected in higher plasma concentrations of aripiprazole and higher dose-adjusted plasma concentrations., Results: Patients co-medicated with duloxetine showed significantly higher plasma concentrations of aripiprazole by 54.2% (p = 0.019). Dose-adjusted plasma concentrations were 45.6% higher (p = 0.001); 12.8% of these patients exhibited aripiprazole plasma concentrations above the upper limit of the therapeutic reference range, in the control group this was only the case for 10.3% of the patients. A positive relationship was found between the daily dose of duloxetine and dose-adjusted plasma concentrations of aripiprazole (p = 0.034). As dehydroaripiprazole concentrations were not available, conclusions for the active moiety (aripiprazole plus dehydroaripiprazole) could not be drawn., Conclusions: Combining duloxetine and aripiprazole leads to significantly higher drug concentrations of aripiprazole, most likely via an inhibition of cytochrome P450 CYP2D6 and to a lesser extent of CYP3A4 by duloxetine. Clinicians have to consider increasing aripiprazole concentrations when adding duloxetine to a treatment regimen with aripiprazole., (© 2023 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Augmentation of antipsychotic treatment with antidepressants represents a common and beneficial treatment strategy in patients suffering from schizophrenia. Combining clozapine and the selective serotonin reuptake inhibitor (SSRI) sertraline represents a clinically important strategy in patients with therapy-resistant schizophrenia, but there is limited knowledge about mutual pharmacokinetic interactions. In the present study, we assessed the impact of clozapine on sertraline plasma concentrations. Based on a therapeutic drug monitoring (TDM) database, sertraline plasma concentrations were compared between two groups: patients receiving a combined treatment with sertraline and clozapine (N = 15) and a matched control group receiving sertraline but no clozapine (N = 17). Group differences with respect to raw and dose-adjusted concentrations were assessed using nonparametric tests. Comedication with clozapine was associated with 67% lower median sertraline plasma concentrations (16 vs. 48 ng/mL; p = .022) and 28% lower median dose-adjusted plasma concentrations (C/D; 0.21 vs. 0.29 (ng/mL)/(mg/day); p = .049) as compared to the control group. Scatter plots revealed a complex relationship between the dosage of clozapine and dose-adjusted sertraline concentrations composed of an initial decrease at clozapine doses below 300 mg, an increase between 300 and 600 mg and a final decrease at 800 mg which was best modeled by a third order polynomial term. Cotreatment with clozapine may lead to reduced sertraline plasma concentrations which may be explained by clozapine-induced gastrointestinal hypo-mobility already present at low doses and cytochrome P450 3A4 inducing properties at high clozapine doses. For this drug combination, clinicians should consider TDM to confirm therapeutically effective plasma concentrations of sertraline., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Physicians look at drug-drug interactions (DDI), or more correctly xenobiotic interactions, in an emotional mixture of fear and interest, due to the apparently countless number of adverse drug effects (ADE) that can occur. The interactions as such are seen as errors; however, interactions cannot be avoided and are an inevitable part of the normal work of physicians. The problem is how to recognize interactions and how to handle them. A xenobiotic interaction can often even improve the effectiveness of a pharmacotherapy and minimize the risks. If all examples of what can possibly happen are not necessarily counted, the flood of information becomes relatively manageable. There are only seven different classes of interactions, four pharmacodynamic and three pharmacokinetic interactions. Currently, there are hotlines and both analogue as well as digital databanks to answer questions and address uncertainties, unfortunately of markedly different quality! Aids, such as therapeutic drug monitoring (TDM) supplement these offers. Every pharmacokinetic interaction can be recognized by determination of the concentration of the active agent. The comprehensive clinical pharmacological TDM report explain the information contained in the concentration of the active agent about the individual patient from whom the blood was drawn. All physicians can learn how to compile the clinical pharmacological TDM report by themselves or they can request it in interdisciplinary cooperation via a council. Medical expertise in handling xenobiotic interactions not only opens the door to adaptation of the pharmacotherapy to the needs of the individual patient but also saves huge budget resources for the healthcare system., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Therapeutic drug monitoring (TDM) aims to individualize drug therapy. This systematic review provides a state-of-the-art overview of the benefits of adding the dose-related reference range (DRR) as a second reference range to the set of tools used by TDM for measurement and evaluation. It discusses alternative pharmacokinetic approaches for individualization of drug therapy., Methods: Literature was searched in PubMed. Textbooks provided Bateman transformations for calculating expected drug concentrations at various times after drug application in "normal patients," that is, the population of phase II clinical trials. The review compiles conditions and prerequisites for these transformations to be valid., Results: Relating a measured drug concentration to the orienting therapeutic reference range provides pharmacodynamic information for improving the benefit-to-risk ratio of desired drug effects versus adverse drug effects. The discriminating DRR considers a patient's individual pharmacokinetic situation. DRR is statistically based on the pharmacokinetic parameters total clearance, time to reach maximal concentrations, and elimination half-life. Relating the measured drug concentration to a range rather than a particular value, DRR determines if individual patients do or do not belong to the population of "normal patients." Once a patient is identified to be outside the population of "normal patients," the clinical-pharmacological TDM report elaborates the cause. It consists of the measured value, the TDM 9-field-board, the elimination pathways table, and a medication recommendation taking into account clinical information. The internet-based platform KONBEST supports editing of the clinical-pharmacological TDM report. It is personally signed and send to the therapist., Conclusions: The DRR embedded into a clinical-pharmacological TDM report allows adjusting a patient's medication to the patient's individual needs (individualization of drug therapy)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) is widely used to guide therapy, avoid toxicity, and assess patient compliance. Commercial immunologic quantification methods are common practice; however, as they are only applicable to one specific drug and prone to cross-reacting metabolites, their practical applicability is limited. In this article, the authors proposed a high-performance liquid chromatography method using ultraviolet detection (HPLC-UV) for simultaneous quantification of 11 ASMs and active metabolites (carbamazepine, felbamate, lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, zonisamide, carbamazepine-10,11-epoxide, and licarbazepine) in serum., Methods: Chromatographic separation was performed on a Phenomenex Luna PFP(2) (3-µm particle size; 150 × 4.6 mm i.d.) analytical column. The mobile phase comprised phosphate buffer (20 mM; pH 3), acetonitrile (ACN), and methanol using gradient elution. Analyses were conducted at 35°C and a 1.3-mL/min flow rate. The detection wavelength for all analytes was 210 nm. The samples were prepared by protein precipitation using ACN., Results: The HPLC-UV method was validated according to the FDA guidelines and applied to measure patient samples in TDM. Calibration curves showed excellent linearity (r2 > 0.99) and covered the entire reference range for each analyte. Intraday and interday imprecisions and inaccuracies were <10% for all samples. Extensive stability testing showed no significant degradation (<15%), and interference measurements additionally ensured clinical applicability. Furthermore, the sensitivity was comparable with that of previously published HPLC methods using mass spectrometry., Conclusions: The authors developed an HPLC-UV method for the simultaneous quantification of 11 ASMs in the human serum and demonstrated its practical applicability in TDM. The method requires only standard laboratory equipment and simple sample preparation, making TDM available in less specialized laboratories., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Knowledge about the impact of body composition features on pharmacokinetics of newer long-acting injectable antipsychotics is limited., Methods: We analyzed steady-state plasma concentrations of paliperidone in different body mass index (BMI), age, sex, and smoking status patient subgroups treated with once-monthly paliperidone palmitate (PP1M). Paliperidone plasma concentrations and dose-adjusted-plasma concentrations (C/D) from a therapeutic drug monitoring (TDM) database of PP1M-treated patients were compared among normal BMI, overweight, and obese patients as well as between females vs. males, elderly vs. non-elderly, and smokers vs. non-smokers using non-parametric tests., Results: In a total of 183 PP1M-treated patients, we found highly variable paliperidone plasma concentrations between individuals but no significant effect of PP1M dose or dosing intervals ( p > 0.05). C/D ratios were similar in 54 obese, 82 overweight, and 47 normal BMI patients ( p > 0.05). Females had 13.7% higher C/D ratios compared to males, yet this difference was not significant ( p > 0.05). No differences were found between elderly vs. non-elderly patients or for smokers vs. non-smokers ( p > 0.05)., Conclusion: Our findings suggest that age, sex, smoking, or body weight may not substantially affect pharmacokinetic indices of PP1M. The high interindividual variation of plasma concentrations implies that TDM may be helpful to enhance PP1M efficacy and tolerability.

Objective: The purpose of this study was to examine the extent to which "potentially inappropriate drugs" (PID) are associated with an increased risk for adverse drug reactions (ADR)., Methods: Data from 304 geriatric psychiatric inpatients was collected. Medical documentation was used to find indications of ADRs. Causal relationship between the ADR and the prescribed drugs was assessed by experts., Results: Almost 30 % of patients received ≥ 1 PID before admission to hospital, in comparison to 22 % at discharge. Increasing number of total prescriptions and the diagnosis of schizophrenia resulted in an increased risk for receiving ≥ 1 PID. Higher age and dementia were protective factors. Patients receiving ≥ 1 PID had a 5-fold increased risk of experiencing ≥ 1 ADR. Risk for an ADR increased with number of PID prescriptions. Patients treated with ≥ 1 PID had a 4-fold increased risk of experiencing severe ADRs. Risk for severe ADRs was 10-fold higher in patients treated with ≥ 2 PIDs., Conclusion: The PRISCUS list predicts significant risk factors for the occurrence of ADRs in the geriatric psychiatric setting., Competing Interests: Johanna Seifert hat an einer Fortbildungsveranstaltung, welche von Otsuka & Lundbeck gesponsert war, teilgenommen. Die anderen Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

To investigate pharmacokinetic correlates of clinical response in patients treated with once-monthly paliperidone palmitate (PP1M) injections at steady state. Plasma concentrations and dose-adjusted-plasma concentrations (C/D) of paliperidone from a naturalistic therapeutic drug monitoring (TDM) database were compared between responders and non-responders using the Clinical Global Impressions-Improvement scale (CGI-I) ratings. Analyses were based on the non-parametric Mann-Whitney U test and the Pearson Chi-squared test (χ 2 ) with a significance level of 0.05. Subgroup analyses were performed separately in patients with schizophrenia spectrum, schizoaffective disorders and bipolar disorders. Comparing 93 responders with 80 non-responders, we detected no significant differences in the proportion of females, age, and body mass index (p's ranging 0.18-0.83); there were more smokers in the group of non-responders (p = 0.04), which also included more patients with bipolar disorders (p = 0.014). Despite the lack of differences for prescribed PP1M doses and dose intervals (p = 0.42 and p = 0.11, respectively), non-responders had higher paliperidone plasma concentrations and C/D levels (p = 0.033 and p = 0.021, respectively). Subgroup analyses did not yield differences for paliperidone plasma and C/D levels between non-responders and responders with schizophrenia spectrum (p = 0.099 and p = 0.14, respectively) and bipolar disorders (p = 0.95 and p = 0.75, respectively); dose-adjusted plasma concentrations were higher in non-responders compared to responders with schizoaffective disorders (p = 0.039), while no differences were reported for plasma levels (p = 0. 15). Our results show that paliperidone plasma concentrations over injection doses may be associated with patterns of clinical response suggesting potential utility of TDM as part of PP1M-based maintenance treatment., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The objective of this study was to investigate associations between pharmacokinetic correlates and once-monthly paliperidone palmitate (PP1M)-related adverse drug reactions (ADRs)., Methods: Plasma concentrations and dose-adjusted plasma concentrations ('concentration-by-dose' [C/D]) of paliperidone from a naturalistic therapeutic drug monitoring database of PP1M-treated patients were compared between patients with ADRs, classified according to the Udvalg for Kliniske Undersogelser side-effect rating scales categories, and patients without ADRs. Analyses included non-parametric tests and a logistic regression model with a significance level set at 0.05., Results: In 172 patients, we found no differences in sex, age, smoking, body mass index, PP1M dose, paliperidone plasma concentrations, and C/D values (p > 0.05) between 44 patients with and 128 patients without PP1M-related ADRs. We did not detect differences when specifying for different types of ADRs (p > 0.05). Injection intervals were shorter in patients with vs patients without ADRs (p = 0.03). The logistic regression did not report effects for sex, plasma concentrations, or C/D values (p > 0.05). Post hoc analyses in male patients receiving PP1M every 28 weeks reported higher paliperidone concentrations and C/D values in patients with vs without ADRs (p = 0.049 and p = 0.022). Within the group of male patients, we found an odds ratio of 3.07 for PP1M-associated ADRs in patients with C/D values above 7.7 (ng/mL)/(mg/day)., Conclusions: Our findings did not reveal distinct patterns of paliperidone concentrations in patients with PP1M-related ADRs. However, male patients receiving PP1M every 28 days with C/D values higher than 7.7 (ng/mL)/(mg/day) showed a higher risk for ADRs, implying that therapeutic drug monitoring may be useful in assessing the risk of PP1M-related ADRs., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Serum concentrations of asymmetric dimethylarginine (ADMA) in patients with schizophrenia, schizoaffective disorder, bipolar disorder, and depression were determined and compared to serum concentrations in healthy individuals. In all psychiatric diseases investigated, the ADMA concentration was elevated compared to the control group. Patients with recurrent depressive disorder had higher ADMA levels than patients with only one depressive episode. No differences between women and men were found. The elevated ADMA levels suggest that ADMA is involved in the pathophysiology of psychiatric diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Patients with mental illnesses are at increased risk of cardiovascular disease-related mortality. Antihypertensive drugs are used particularly for the prophylaxis and treatment of cardiovascular diseases. In combination with psychiatric medication there is a potential for interaction, which can impair the achievement of therapeutic goals., Objective: The prescription behavior for antihypertensive drugs in psychiatric clinics and practices in German-speaking countries as well as the interaction potential with psychotropic drugs were investigated., Methods: The AGATE "index day" database, which anonymously stores patient data on age, sex, psychiatric main diagnosis as well as the prescribed commercial preparations collected in AGATE institutions (hospitals and community practitioners), was analyzed. The possible interactions were analyzed with PSIAC., Results: Between 1 January 2012 and 31 December 2016, 27% of all 21,980 patients recorded had a prescription for at least 1 antihypertensive drug, rising to 72% among patients over 80 years old. Of the patients treated with antihypertensive drugs, 48% received antihypertensive monotherapy. The importance of antihypertensive drug combination treatment increased with age. A median of 7 active substances were prescribed to the patients which mathematically results in 21 interactions. The simultaneous administration of psychotropic and antihypertensive drugs can result in an increased risk of hypotension, insufficient blood pressure reduction or QTc prolongation., Conclusion: Antihypertensive drugs are important in the treatment of psychiatric patients. An interaction test should be performed if pharmacotherapy is to be supplemented or changed. Where appropriate, measures to improve drug treatment safety should be considered.

Background and Objective: Hypersalivation is a common, clozapine-related adverse drug reaction with a serious impact on quality of life. Pharmacokinetic correlates of clozapine-related hypersalivation have evaded attention. The purpose of this study was to compare pharmacokinetic parameters between clozapine-treated patients with vs. without hypersalivation from a large therapeutic drug monitoring database., Methods: Out of a large therapeutic drug monitoring dataset of clozapine-treated patients, we compared a group of patients with hypersalivation (n = 72) and a control group of patients without any adverse reactions in this regard (n = 323). Comparisons included plasma concentrations and concentrations-by-dose as well as demographic characteristics between groups. Post-hoc analyses were performed separately in smokers and non-smokers. We used the non-parametric Mann-Whitney U test and the chi-square test, while effects of confounders were assessed using a bootstrapping analysis of covariance., Results: Patients with hypersalivation had higher clozapine plasma concentrations and concentrations-by-dose (p < 0.001 for the Mann-Whitney U test in both cases). Groups did not differ regarding demographic characteristics except for clozapine daily dose and percentage of smokers (p = 0.005 for the Mann-Whitney U test and p = 0.028 for the chi-square test, respectively). There were fewer smokers across patients with hypersalivation compared with patients without and daily doses were higher in patients with hypersalivation. After analysis of covariance, differences remained for both plasma concentrations and concentrations-by-dose (p < 0.001 for both). Post hoc analyses in smokers and non-smokers separately reported similar findings., Conclusions: Elevated clozapine plasma concentrations and higher concentrations-by-dose were observed in patients with hypersalivation. A potential role for therapeutic drug monitoring in the prevention or management of clozapine-related hypersalivation is suggested.

Aim: Comorbidity of pain and depression or anxiety is a challenging clinical phenomenon, often requiring the concurrent application of antidepressant and analgesic drugs. Growing evidence suggests that the analgesic metamizole exhibits cytochrome P450 inducing properties. In the present study, we assessed the impact of metamizole and ibuprofen on plasma concentrations of the selective serotonin reuptake inhibitor sertraline., Methods: Out of a therapeutic drug monitoring (TDM) database, three groups of patients were compared: patients receiving sertraline and metamizole (n = 15), patients receiving sertraline and ibuprofen (n = 19), and a matched control group without one of the analgesics (n = 19)., Results: Metamizole was associated with 67% lower median sertraline plasma concentrations compared to the control group (14 vs 42 ng/mL, P < 0.001). In contrast, differences between the ibuprofen group and the control group did not reach statistical significance (31 vs 42 ng/mL, P = 0.128). Moreover, the metamizole group demonstrated lower dose-adjusted drug concentrations than the ibuprofen group (0.10 vs 0.26 (ng/mL)/(mg/day), P = 0.008). Finally, the metamizole group exhibited a higher proportion of patients whose sertraline concentrations were below the therapeutic reference range (40% in the metamizole group, 5% in the ibuprofen group, 0% in the control group, P = 0.005) indicating therapeutically insufficient drug concentrations., Conclusion: Our findings support preliminary evidence that metamizole acts as a potent inductor of cytochrome P450 isoenzymes CYP2B6 and CYP3A4. We observed a clinically meaningful pharmacokinetic interaction between metamizole and sertraline, leading to insufficiently low sertraline drug concentrations. Clinicians should therefore consider alternative drug combinations or apply TDM-guided dose adjustment of sertraline., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Knowledge regarding the impact of body composition measures on pharmacokinetics of antipsychotics is limited., Aims: Our aim was to investigate the impact of body weight and body mass index on clozapine pharmacokinetics using a therapeutic drug monitoring database., Methods: A large therapeutic drug monitoring dataset of clozapine plasma concentrations considering three patient subgroups was analysed: a control group (CLZ 0 , 20-30 kg/m 2 , n =266), a group with high body mass index (CLZ high , body mass index ⩾30 kg/m 2 , n =162) and with low body mass index values (CLZ low , body mass index <20 kg/m 2 , n =27). Comparisons of plasma and dose-adjusted plasma concentrations (C/D) of clozapine were based on the Spearman's correlation ( r s), Kruskal Wallis and Mann-Whitney-U tests. For percentages we used the Pearson chi-square test (χ 2 ). To assess effects of confounders we used bootstrapping analysis of covariates., Results/outcomes: Regarding demographic characteristics, groups differed only for sex percentage with more females than males in CLZ low and CLZ high compared to CLZ 0 ( p =0.001 for χ 2 test). Plasma and C/D values were positively associated with body mass index ( r s=0.108, p =0.022 and r s=0.156, p =0.001 respectively). Intergroup differences were observed for plasma and dose-adjusted concentrations of clozapine ( p =0.031 and p =0.029 for Kruskal Wallis respectively): post-hoc pairwise comparisons showed higher plasma concentrations and C/D of clozapine in CLZ high compared to CLZ 0 ( p =0.014 and p =0.007 respectively for Mann-Whitney U-test), by mean 21 and 18%, respectively. Differences for C/D values remained after accounting for sex ( p =0.02)., Conclusions/interpretation: In obese patients, bioavailability, distribution or elimination of clozapine may be altered due to increased clozapine deposits in fat tissue and hepatic enzyme activity changes.

Introduction: Major smoking effects have been reported for a series of psychotropic agents, mainly including substrates of CYP450 1A2, although smoking may also affect alternative metabolic pathways. To our knowledge, smoking effects on paliperidone pharmacokinetics have not been assessed yet., Methods: We compared plasma concentrations of paliperidone as well as dose-corrected-plasma concentrations (C/D) from a naturalistic database between smokers and nonsmokers using nonparametrical tests, such as the Mann-Whitney U-test (MWU). Additionally, we compared light and heavy smokers with nonsmokers separately., Results: Comparing 55 smokers with 37 nonsmokers treated with oral paliperidone, no differences in the percentage of females, age, body weight, body mass index, and daily paliperidone dose were reported (p=0.709 for χ 2 , p=0.26, p=0.38, p=0.67, and p=0.8 for MWU). No differences were detected in plasma concentrations or C/D values (p=0.50 and p=0.96 for MWU). Likewise, differences in daily dose, plasma concentrations, or C/D values were not significant between light smokers (n=17) and nonsmokers (p=0.61, p=0.81, and p=0.33 for MWU) or heavy smokers (n=22) and nonsmokers (p=0.874, p=0.38, and p=0.59; MWU in all cases)., Discussion: Paliperidone is not affected by smoking, and paliperidone dose-adjustments in smokers may not be necessary. This may be seen as an essential difference to risperidone, whose cytochrome-mediated metabolism might be affected by smoking., Competing Interests: Dr. Haen received speaker’s or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is managing director of AGATE. He reports no conflict of interest with this publication. Dr. Hiemke has received speaker’s or consultancy fees from Janssen-Cilag, Lohmann Transdermal Systems, and Servier. He reports no conflict of interest with this publication. Dr. Conca has served as a consultant for Lilly, Bristol-Myers Squibb, and Pfizer. He has served on the speakers’ bureau of Lilly, BMS, Astra Zeneca, Lundbeck, Italfarma, and Janssen. Dr. Gründer has served as consultant and advisory board member for the following companies and institutions: Allergan, Boehringer Ingelheim, Eli Lilly, IQWiG, Janssen-Cilag, Lundbeck, Otsuka, Recordati, SAGE, and Takeda. He has received honoraria as a speaker for Gedeon-Richter, Janssen-Cilag, Lundbeck, Neuraxpharma, Otsuka, and Recordati and funding for clinical trials from Boehringer Ingelheim, Lundbeck, and Saladax. He is the founder and shareholder of Brainfoods GmbH and Mind and Brain Institute GmbH. Dr. Paulzen has received speaker’s fees from Neuraxpharm and Lundbeck. He reports no conflict of interest with this publication. All other authors report no conflicts of interests., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Clozapine is an effective antipsychotic drug for treatment-resistant schizophrenia. Sertraline is a widely prescribed antidepressant and often concomitantly applied to address negative symptoms or depression. However, data on interactions between clozapine and sertraline are inconsistent. The aim of our study was to evaluate pharmacokinetic interactions between clozapine and sertraline analysing a therapeutic drug monitoring database of 1644 clozapine-medicated patients. We compared four groups: non-smokers (n = 250) and smokers (n = 326) with co-medication without known effects on cytochrome P450 and without sertraline, and non-smokers (n = 18) and smokers (n = 17) with sertraline co-medication. Measured and dose-corrected concentrations (C/D) of clozapine were compared between the groups using non-parametrical tests with a significance level of 0.05. Post hoc analyses included pairwise comparisons to account for smoking status. Although we detected significant differences for clozapine levels and C/D values between study groups (P < .001 for Kruskal-Wallis test in both cases), post hoc analyses revealed no differences for concentrations and C/D values of clozapine (P > .05 for Mann-Whitney U test in both cases). A negative correlation between the sertraline dose and the clozapine concentration was found in non-smokers (Spearman's rank correlation, rs = -0.535, P = .048). A potential pharmacokinetic interaction between clozapine and a standard therapeutic sertraline dose seems to be of minor clinical importance., (© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly. The main aim of this article is to aid clinicians who routinely prescribe antipsychotics to successfully apply TDM in routine clinical practice in order to help optimize the efficacy and safety of those antipsychotics., Participants: Participants were clinicians and researchers, members of the American Society of Clinical Psychopharmacology, and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association of Neuropsychopharmacology and Pharmacopsychiatry)., Evidence: TDM literature on antipsychotics was critically reviewed to provide a condensed clinical decision-making algorithm with therapeutic reference ranges for blood antipsychotic levels, within which patients are most likely to respond and tolerate treatment, although TDM is not equally recommended/supported for all antipsychotics., Consensus Process: A preliminary draft was prepared and circulated to the writing group members. Consensus was achieved in all cases, and resulting recommendations focused on following areas: steady-state and sampling time, levels of recommendations, indications, therapeutic reference ranges and laboratory alert levels, practical issues, and interpretation, as well as limitations., Conclusions: The utilization of TDM as a tool for problem solving in antipsychotic treatment offers a unique method to improve safety and efficacy. This consensus statement summarizes essential information on the routine use of TDM for antipsychotics and encourages clinicians to perform TDM with the appropriate indications as part of the clinical decision-making process., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Background: Polypharmacy including somatic medications such as proton pump inhibitors is a common phenomenon in psychiatric care. The aim of this study was to evaluate the pantoprazole effects on clozapine metabolism., Methods: A large therapeutic drug-monitoring database containing plasma concentrations of CLZ was analyzed. The results were stratified into four groups: a non-smoking (n=250) and a smoking group (n=326), and two groups co-medicated with pantoprazole: non-smokers (n=26) and smokers (n=29). The analysis was based on the non-parametrical Mann-Whitney U test (M-W-U) with a significance level of 0.05., Results: Differences reached statistical significance for pharmacokinetic parameters between CLZ monotherapy and co-medication with pantoprazole neither in smokers nor in non-smokers (p>0.05 for M-W-U in pairwise comparisons). In patients with clozapine monotherapy, smokers had a higher daily dosage of CLZ compared to non-smokers (mean dosage 363±181 vs. 291±145 mg/day, p<0.001 for M-W-U)., Conclusions: Adding pantoprazole to an ongoing treatment with clozapine does not alter the metabolism of clozapine to a significant extent., Competing Interests: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ekkehard Haen received speaker’s or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is managing director of AGATE, a non-profit working group to improve drug safety and efficacy in the treatment of psychiatric diseases. He reports no conflict of interest with this publication. Gerhard Gründer has served as a consultant and advisory board member during the last three years for the following companies and institutions: Allergan, Boehringer Ingelheim, Eli Lilly, IQWiG, Janssen-Cilag, Lundbeck, Otsuka, Recordati, Roche, Servier, and Takeda. He has received honoraria as a speaker for Janssen-Cilag, Lundbeck, Neuraxpharma, Otsuka and Recordati. He has received funding for clinical trials from Boehringer Ingelheim, Lundbeck and Saladax. He is the founder and partner of Brainfoods GmbH, InMedicon GmbH, and Mind and Brain Institute GmbH. Christoph Hiemke has received speaker or consultancy fees from the following pharmaceutical companies: Astra Zeneca, Janssen-Cilag, Pfizer, Lilly and Servier. He is managing director of psiac GmbH, which provides an Internet-based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Maxim Kuzin received travel grants from Sunovion Pharmaceutical (Basel, Switzerland) and Otsuka Pharmaceutical (Glattburgg, Switzerland). He also received a travel grant and remuneration to participate on the speaker’s board of Lundbeck (Zurich, Switzerland). All other authors report no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Therapeutic drug monitoring helps clinicians in choosing the right drug and adjust its dose in specific patients. To this end, we aimed to assess time patterns of risperidone and its metabolite, 9-hydroxyrisperidone, in children and adolescents with oppositional defiant and/or conduct disorder., Methods: We measured plasma concentrations of risperidone and 9-hydroxyrisperidone, their sum (active moiety, AM) and ratio, as well as plasma concentrations corrected for daily dose (C/D), from 140 children/adolescents with the above-mentioned disorders. We used Student's t test to compare females versus males, patients under versus over 16-year-old, patients with lower versus higher than the median body weight, and patients with lower versus higher than the median body mass index (BMI). Two mixed-effects logistic regression models were fitted for risperidone/9- hydroxyrisperidone ratio and AM, respectively, by considering risperidone daily dose and patients' demographic characteristics., Results: Females had higher 9-hydroxyrisperidone and AM plasma concentrations than males ( p = 0.004 and p = 0.034). Younger patients had lower risperidone plasma concentration and risperidone/9-hydroxyrisperidone ratio ( p = 0.02 and p = 0.021), but higher C/D 9-hydroxyrisperidone and AM than older patients ( p = 0.013 and p = 0.043). Lower-weight patients had lower plasma risperidone and risperidone/9-hydroxyrisperidone ratio ( p = 0.014 and p = 0.019), but higher C/D 9-hydroxyrisperidone concentration than heavier patients ( p = 0.03). All these results could be accounted for by daily dose. Patients with lower and higher BMI did not differ significantly. Regression analyses showed that only risperidone daily dose predicted risperidone/9-hydroxyrisperidone ratio, whereas risperidone daily dose, sex, and age predicted AM., Conclusion: Clinicians prescribing risperidone need to consider sex, age, and weight, but not BMI when adjusting daily doses.

Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy)., Methods: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties., Results: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being., Conclusions: Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

To address the potential correlation between plasma concentrations of venlafaxine (VEN), its active metabolite O-desmethylvenlafaxine (ODVEN) and the active moiety, AM, (ODVEN + VEN) and adverse drug reactions (ADR) in a large naturalistic sample of in- and outpatients. We compared plasma concentrations of VEN, ODVEN and AM and dose-adjusted (C/D) levels as well the ODVEN/VEN ratios between patients complaining ADRs, following the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 114) and patients without ADRs (control group, n = 688) out of a naturalistic database. We also investigated potential pharmacokinetic correlates of the four UKU categories by comparing patients complaining ADRs with those who did not. Based on previous literature we applied different ODVEN/VEN ratio values as cut-offs to split our sample into two groups at a time and compare frequencies of ADRs between the groups. No differences for demographic and pharmacokinetic variables including plasma and C/D concentrations as well as ODVEN/VEN ratios were observed between study groups. Neither the comparisons between females and males nor between elderly and non-elderly patients revealed significant differences (p > 0.05 in all cases). No differences were also reported exploring the patients complaining ADRs from the 4 UKU categories separately. After applying various ODVEN/VEN cut-offs, groups did not display differences in frequencies of ADRs (p > 0.05 in all cases). Our findings do not demonstrate a direct link between venlafaxine metabolism measures and ADRs. Therefore, additional dimensions are needed to be considered in future trials aiming to disentangle the involved aspects of ADRs in patients receiving venlafaxine.

Objective: The aim of this study was to ensure patients' safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations of polypharmacy is invaluable. This study is to uncover the potential of pharmacokinetic interactions between venlafaxine and trimipramine in a naturalistic sample., Methods: Out of a therapeutic drug monitoring database with plasma concentrations of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV), we considered two groups of patients receiving venlafaxine without known cytochrome P450 confounding medications, taking solely venlafaxine: V0 (n = 905), and a group of patients co-medicated with trimipramine, VTRIM (n = 33). For VEN, ODV and active moiety (sum of VEN + ODV) plasma concentrations and dose-adjusted concentrations as well as ODV/VEN ratios were compared between groups using the Mann-Whitney U test with a significance level of 0.05., Results: Patients co-medicated with trimipramine had higher plasma concentrations of VEN (183.0 vs. 72.0, +154%, P = 0.002) and AM (324.0 vs. 267.5, +21%, P = 0.005) and higher dose adjusted plasma concentrations than patients in the control group (P = 0.001 and P = 0.003). No differences were found for ODV and C/D ODV (P < 0.05 for both comparisons). The metabolite to parent ratio, ODV/VEN, was significantly lower in the VTRIM group (1.15 vs. 2.37, P = 0.012)., Conclusion: Findings suggest inhibitory effects of trimipramine on venlafaxine pharmacokinetics most likely via an inhibition of CYP 2D6 or by saturated enzyme capacity. The lack of in vitro data hampers the understanding of the exact mechanisms. Clinicians should be aware of drug-drug interactions when combining these agents. Therapeutic drug monitoring helps to ensure treatment efficacy and patients' safety.

Purpose: To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of active moiety, AM (sum of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN))., Methods: Applying a regression model, plasma concentrations and plasma concentrations corrected-by-dosage (C/D) for AM were included as independent variable with Clinical Global Impressions-Improvement (CGI-I) scale ratings as dependent variable. Moreover, AM, VEN, and ODVEN were compared between treatment responders and non-responders, defining response as much or very much improved on the CGI-I scale based on the non-parametric Mann-Whitney U (M-W-U) test with a significance level of 0.05., Results: No correlations were found between AM and C/D AM plasma concentrations and CGI-I ratings (regression coefficient 0.0, CI 0.000, 0.001, p = 0.492 for AM and 0.047, CI - 0.065, 0.159, p = 0.408 for C/D AM). Venlafaxine daily dosage did not differ between responders and non-responders (217.7 ± 76.9 vs. 222.0 ± 72.7 mg/day, p = 0.45 for M-W-U). Responders displayed lower ODVEN (p = 0.033) and AM (p = 0.031) plasma concentrations than non-responders (p = 0.033 and 0.031, respectively for M-W-U). No other differences were detected. Using a cut-off level of 400 ng/mL for AM concentrations, a higher percentage of responders was reported in the group of patients with AM < 400 ng/mL (13.04%) compared to patients with AM > 400 ng/mL (8%) (p = 0.038)., Conclusions: Higher ODVEN and AM concentrations in non-responders than in responders indicate that treatment escalation above upper thresholds of therapeutic reference ranges of venlafaxine is not promising. Hence, the therapeutic reference range for venlafaxine can help in improving outcomes in a measurement-based care model that takes advantage of therapeutic drug monitoring.

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.

We assessed the effect of body weight and BMI on plasma concentrations of venlafaxine (VEN), O-desmethylvenlafaxine (ODVEN), active moiety (AM=VEN+ODVEN), and dose-corrected plasma concentrations (C/D). A database containing concentrations of VEN and ODVEN including 737 of 1594 eligible patients was analyzed. Analyses included sex, body weight, and BMI as well as concentrations of VEN, ODVEN, AM, and C/D. A positive correlation was detected between body weight and daily dosage (rs=0.168, P<0.001). A negative correlation was found between body weight and AM (rs=-0.124, P=0.001) and ODVEN (rs=-0.137, P<0.001). Negative correlations were also found between body weight and C/D ratios (C/D VEN: rs=-0.134, P<0.001, C/D ODVEN: rs=-0.239, P<0.001, C/D AM: rs=-0.256, P<0.001). No correlations were detected between BMI and concentrations for VEN, ODVEN, and AM. Comparing low-BMI (<20 kg/m²), medium-BMI (20-29.9 kg/m²), and high-BMI (≥30 kg/m²) groups, higher values of some pharmacokinetic variables in the lower BMI group did not remain significant after controlling for sex. Women had higher VEN, ODVEN, AM, and C/D values for AM, VEN, and ODVEN than men (P<0.001 for all comparisons). Our results highlight the role of different pharmacokinetically relevant parameters and foremost of sex as mediators for the effect of BMI on VEN metabolism.

Background: Amlodipine (AMLO) and ramipril (RAMI) belong to the most prescribed drugs in patients with hypertension, a condition also encountered in depression. Venlafaxine may worsen hypertension because of noradrenergic properties. Although of special clinical relevance, data on pharmacokinetic interactions between AMLO, RAMI, and venlafaxine (VEN) are lacking., Methods: Two TDM databases consisting of plasma concentrations of VEN and its active metabolite O-desmethylvenlafaxine (ODVEN) were analyzed. We considered a group of patients comedicated with AMLO, VAMLO (n = 22); a group comedicated with RAMI, VRAMI (n = 20); and a 4:1 control group age matched to the VAMLO group receiving VEN without confounding medications, V0 (n = 88). Plasma concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN); metabolic ratio (ODVEN/VEN); and dose-adjusted plasma concentrations (C/D) were compared using nonparametric tests., Results: Groups did not differ in daily VEN dose, age, or sex. The metabolic ratio (ODVEN/VEN) was lower in the AMLO group (P = 0.029), whereas the RAMI group showed lower values for ODVEN (P = 0.029). All other parameters showed no significant differences., Conclusions: Significantly lower values for the metabolic ratio in the AMLO group are unlikely to be explained by cytochrome P450 (CYP) 3A4 and weak CYP2D6 inhibition by AMLO. Other factors such as differences in CYP2D6 polymorphisms and metabolizer status may better explain the findings. Ramipril showed modest effects with changes in ODVEN concentrations that did not remain significant after dose-adjusted comparisons.

Background: For certain psychotropic drugs, such as clozapine or olanzapine, the influence of smoking on drug metabolism is well studied. Tobacco smoke increases the metabolism of drugs that are substrates for cytochrome P450 (CYP) 1A2 due to CYP induction. The antidepressant duloxetine, acting as a serotonin-norepinephrine reuptake inhibitor, is mainly metabolized via CYP1A2. To date, little is known about the influence of smoking on serum duloxetine concentrations., Methods: A therapeutic drug monitoring database consisting of plasma concentrations of duloxetine collected from January 2013 to June 2017 was analyzed. A group of nonsmoking patients undergoing treatment with duloxetine (n = 89) was compared to a group of active smokers also receiving duloxetine (n = 36). Serum concentrations of duloxetine and dose-adjusted serum concentrations were compared using non-parametric tests., Results: Groups did not differ concerning sex (P = .063), but the group of active smokers was younger (P < .001) and received higher daily doses of duloxetine (P = .001). Smokers showed significantly lower median serum duloxetine concentrations (38.4% lower, P = .002) and 53.6% lower dose-adjusted serum concentrations (0.325 [ng/mL]/[mg/d] in smokers vs 0.7 [ng/mL]/[mg/d] in nonsmokers, P < .001)., Conclusions: Despite higher daily doses, smokers had considerably lower serum duloxetine concentrations. The induction of CYP1A2 by tobacco smoke is a clinically relevant factor for drugs that are substrates for CYP1A2. Clinicians should actively assess smoking status, inform patients about the effect of smoking on duloxetine metabolism, and anticipate higher serum concentrations in the case of smoking cessation. Therapeutic drug monitoring ensures treatment efficacy by enabling the personalizing of treatment, as smokers need higher duloxetine doses to target serum concentrations within the therapeutic reference range., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic interactions between venlafaxine and quetiapine have not been studied yet. A therapeutic drug monitoring database containing serum concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. Two groups of patients were compared: venlafaxine monotherapy V 0 (n = 153) and co-medication with quetiapine, V QUE (n = 71). Serum concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN), metabolite to parent compound ratio (ODVEN/VEN) and dose adjusted serum concentrations were compared using non-parametrical tests without information on CYP2D6 genotype. The two groups did not differ in terms of the daily dosage of venlafaxine, age, or sex. Median serum concentrations in the quetiapine group showed significantly, 15.8% and 29.3% higher values for AM and ODVEN (p = 0.002, Cohen's d = 0,41; p = 0.003, d = 0,44), respectively. Dose adjusted serum concentrations of active moiety and ODVEN revealed comparable differences (p = 0.038, d = 0,32; p = 0.015, d = 0,28) with significantly higher values in the co-medicated group. Significantly higher values for ODVEN and AM suggest a reduced clearance of ODVEN and active moiety when quetiapine is co-administered. This may be a consequence of a reduced metabolism of venlafaxine to the inactive metabolite N-desmethylvenlafaxine via CYP3A4, the main metabolizing enzyme for quetiapine, and a shift towards a higher proportion of the active metabolite ODVEN. Therapeutic drug monitoring is recommended in the case of co-medication to ensure clinical efficacy and patient safety. Although the increase of AM is moderate, we consider it relevant for clinicians given the prevalence of concomitant medication of quetiapine and venlafaxine., (Copyright © 2018 Elsevier Inc. All rights reserved.)

BACKGROUND AND OBJECTIVE: An increasing trend in prescribing proton pump inhibitors (PPIs) inevitably increases the risk of unwanted drug-drug interactions (DDIs). The aim of this study was to uncover pharmacokinetic interactions between two PPIs-omeprazole and pantoprazole-and venlafaxine., Methods: A therapeutic drug monitoring database contained plasma concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine. We considered three groups: a group of patients who received venlafaxine without confounding medications (non-PPI group, n = 906); a group of patients who were comedicated with omeprazole (n = 40); and a group of patients comedicated with pantoprazole (n = 40). Plasma concentrations of venlafaxine, O-desmethylvenlafaxine and active moiety (venlafaxine + O-desmethylvenlafaxine), as well as dose-adjusted plasma concentrations, were compared using non-parametrical tests., Results: Daily doses of venlafaxine did not differ between groups (p = 0.949). The Mann-Whitney U test showed significantly higher plasma concentrations of active moiety, as well as venlafaxine and O-desmethylvenlafaxine, in both PPI groups [p = 0.023, p = 0.011, p = 0.026, +29% active moiety, +27% venlafaxine, +36% O-desmethylvenlafaxine (pantoprazole); p = 0.003, p = 0.039 and p < 0.001, +36% active moiety, +27% venlafaxine, +55% O-desmethylvenlafaxine (omeprazole)]. Significantly higher concentration-by-dose (C/D) values for venlafaxine and active moiety were detected in the pantoprazole group (p = 0.013, p = 0.006, respectively), while in the omeprazole group, C/D ratios for all three parameters-venlafaxine, O-desmethylvenlafaxine and active moiety-were significantly higher (p = 0.021, p < 0.001 and p < 0.001, respectively)., Conclusions: Significantly higher plasma concentrations for all parameters (venlafaxine, O-desmethylvenlafaxine, active moiety) suggest clinically relevant inhibitory effects of both PPIs, most likely on the cytochrome P450 (CYP) 2C19-mediated metabolism of venlafaxine. The findings might be the result of different degrees of CYP2C19 involvement, therefore the inhibition of CYP2C19 by both PPIs may lead to an increased metabolism via CYP2D6 to O-desmethylvenlafaxine.

Objectives: 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., Methods: 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., Results: 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., Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Background: Neuroleptic malignant syndrome (NMS) is a rare but severe undesired complication of psychopharmacological treatment. The mortality has shown a significant decrease since its first description. Knowledge of NMS is important for every clinician because of the need for rapid diagnosis and treatment., Objective: This article presents a review and critical appraisal of the current study situation for NMS. Recommendations for diagnostics, differential diagnostics and treatment are presented particularly from a clinical perspective., Material and Methods: A literature review with the keywords "neuroleptic malignant syndrome", "Malignes neuroleptisches Syndrom" and various psychotropic drugs was performed in PubMed. The database of the Working Group for Pharmaceutical Treatment of Psychiatric Diseases (Arbeitsgemeinschaft für Arzneimitteltherapie bei psychiatrischen Erkrankungen, AGATE) was analyzed with respect to registered cases of the undesired side effect NMS., Results: In contrast to the first description, which also led to the name, there are now case reports of clinical conditions similar to NMS, which were obviously triggered by several groups of psychotropic drugs not just antipsychotic agents (German: Neuroleptika). Treatment recommendations exist whereby the effectiveness cannot always be scientifically substantiated; however, it is still undisputed that a rapid initiation of treatment is of great importance., Discussion: The psychiatrist must be familiar with the symptoms of NMS, its differential diagnosis and the therapeutic options for a rapid and effective treatment. Further studies are urgently needed for scientific substantiation of the pathophysiology of NMS and to develop evidence-based guidelines for treatment.

Background: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample., Methods: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V 0 (n = 905), a group of patients co-medicated with doxepin, V DOX (n = 25) and a second group, co-medicated with mirtazapine, V MIR , n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared., Results: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism., Conclusions: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy., Limitations: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We aimed to explore the differences in the pharmacokinetics of risperidone between oral and long-acting injectable (LAI) formulations using a large database of therapeutic drug monitoring (TDM). Plasma concentrations of risperidone (RIS), its active metabolite (9-OH-RIS) and the active moiety (AM) (RIS+9-OH-RIS), their concentration-to-dose (C/D) ratios and ratio of RIS/9-OH-RIS (an index of CYP2D6 metabolic activity) were used to compare patients receiving risperidone orally (n = 851) and those treated with LAI RIS (n = 63). Patients taking CYP inducers or inhibitors or with liver/renal impairment were eliminated. Our study demonstrated that patients on LAI RIS, despite slightly higher RIS doses in the oral group, showed no significant differences in total AM or 9-OH-RIS. Conversely, RIS concentration, RIS C/D ratio and total C/D ratio were slightly higher in the LAI RIS group, reaching significance due to the large sample size. More importantly, the median ratio of RIS/9-OH-RIS was 0.52 in LAI RIS vs. 0.25 in the oral group, providing a significant difference (p < 0.001). After controlling for confounding factors, we replicated the RIS/9-OH-RIS ratio increases in patients with LAI RIS, probably reflecting a decrease in first-pass metabolism. More studies are required to establish the clinical use of TDM for patients on LAI RIS., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs., Competing Interests: Christoph Hiemke has received speaker’s and consultancy fees from Janssen, Stada, Servier. He is managing director of the psiac GmbH (www.psiac.de) which provides an internet based drug-drug interaction program. Pierre Baumann has received speaker’s or consultancy fees from almost all pharmaceutical companies selling psychotropic drugs in Switzerland. Niels Bergemann received speaker‘s or consultancy fees and/or educational grants from AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Otsuka, Pfizer, Servier. Andreas Conca has served as a consultant for Lilly, Bristol-Myers Squibb, Pfizer. He has served on the speakers’ bureau of Lilly, BMS, Astra Zeneca, Lundbeck, Italfarma, Janssen. Gabriel Eckermann has received speaker’s fees from almost all pharmaceutical companies selling psychotropic drugs in Germany. He is shareholder of the psiac GmbH (www.psiac.de), which provides an internet based drug-drug interaction program. Karin Egberts participated in performing clinical trials for AstraZeneca, Janssen-Cilag, Lilly, Shire and has received research grants pertaining to pharmacovigilance in children and adolescents from the German Federal Institute for Drugs and Medical Devices. Ursula Havemann-Reinecke has received speaker’s and consultancy fees and unrestricted educational grants from AstraZeneca, Bristol-Myers Squibb, Cephalon, Essex, Janssen Cilag, Lundbeck, Pfizer, Schering-Plough, Wyeth. Ekkehard Haen is chairman and managing director of the AGATE (www.amuep-agate.de) that supports reasonable and economic drug therapy. He is shareholder of the psiac GmbH (www.psiac.de), which provides an internet based drug-drug interaction program. Manfred Gerlach has received research grants pertaining to pharmacovigilance in children and adolescents from the German Federal Institute for Drugs and Medical Devices. He has also received royalties from Springer Vienna for editing a German and English textbook on child and adolescent psychiatry. Gerhard Gründer has served as a consultant for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Otsuka. He has served on the speakers’ bureau of Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Cilag, Otsuka, Pfizer, Servier, Wyeth. He has received grant support from Alkermes, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson. He is co-founder of Pharma-Image – Molecular Imaging Technologies GmbH. Eveline Jaquenoud is a member of mediQ (www.mediq.ch) which provides an internet based drug-drug interaction program for psychiatry. Gerd Laux has received speaker’s or consultancy fees or unrestricted educational grants from AstraZeneca, Bayer, Eli Lilly, Lundbeck, Merz, Pfizer, Servier, Wyeth. Thomas Messer has received speaker’s or consultancy fees or unrestricted educational grants from Eli Lilly, Bristol-Myers Squibb, Janssen, Servier, Pfizer, Lundbeck, Bayer Vital Health Care. Matthias J. Müller has received speaker’s or consultancy fees from Janssen, Lundbeck, Servier. Bruno Pfuhlmann has received speaker’s or consultancy fees from AstraZeneca, Janssen, Pfizer. Sven Ulrich is an employee of Ariston Pharma GmbH, Berlin, Germany. Gerald Zernig has received speaker’s or consultancy fees or educational grants from AlcaSynn, AstraZeneca, Bio-Rad, Bristol-Myers Squibb, Eli Lilly, Lundbeck, Mundipharma, Novartis, Pfizer, Wyeth. Hans Willi Clement, Jürgen Deckert, Katharina Domschke, Christine Greiner, Gudrun Hefner, Renate Helmer, Ger Janssen, Rainold Mössner, Michael Paulzen, Peter Riederer, Alois Saria, Bernd Schoppek, Georgios Schoretsanitis, Markus Schwarz, Margarete Silva Gracia, Benedikt Stegmann, Werner Steimer, Julia C. Stingl, Manfred Uhr, Stefan Unterecker and Roland Waschgler were not supported by pharmaceutical industry., (© Georg Thieme Verlag KG Stuttgart · New York.)

A simple, accurate and selective column-switching high-performance liquid chromatography (HPLC) method was developed and validated for simultaneous quantification of six beta-blockers (metoprolol, timolol, bisoprolol, propranolol, carvedilol and nebivolol), three of their metabolites (α-hydroxy metoprolol, N-desisopropyl propranolol and 4'-hydroxy carvedilol 4-HCAR), three antipsychotics (olanzapine, clozapine and quetiapine) and three of their metabolites (N-desmethyl olanzapine, N-desmethyl clozapine and N-desalkyl quetiapine) in human serum. After pretreatment on a Merck LiChrospher RP-4 ADS column (25 μm), drugs were separated on a Phenomenex Gemini Phenyl Hexyl 110 A column (250 × 4.6 mm, 5 μm) using a gradient mixture of acetonitrile and potassium dihydrogen phosphate buffer pH 3.1 (containing 10% methanol) as a mobile phase at a flow rate of 1 mL/min. The total analysis time was 40 min. For detection of the analytes, four different UV wavelengths were used: 215, 226, 242 and 299 nm. The method was validated according to the guidelines of the Society of Toxicology and Forensic Chemistry in terms of selectivity, linearity, accuracy, precision and stability and successfully applied for the analysis of the 15 described analytes in human serum., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Although clinically widespread, scientific evidence for antipsychotic polypharmacy is still limited. Combining different drugs increases the potential for drug-drug interactions, enhancing the risk of adverse drug reactions. We aimed to unravel the potential pharmacokinetic interactions between risperidone (RIS) and perazine., Methods: Using a therapeutic drug monitoring database containing plasma concentrations of RIS and its active metabolite [9-hydroxyrisperidone (9-OH-RIS)], we considered two groups: a group of patients under antipsychotic monotherapy with RIS (n = 40) and a group of patients that was comedicated with perazine (n = 16). Groups were matched for demographic characteristics and daily dosage of RIS. Plasma concentrations, concentrations corrected for the dose (C/D) of RIS, 9-OH-RIS and the active moiety (RIS + 9-OH-RIS), as well as the metabolic ratios of concentrations of 9-OH-RIS/RIS, were compared using nonparametric tests., Results: All parameters other than plasma concentrations and the C/D ratio of 9-OH-RIS differed between groups. Median values for plasma concentrations of the active moiety and C/D of the active moiety were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Differences were driven by variations in the plasma concentrations and C/D of RIS, which were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Metabolic ratios were lower in the perazine group (P = 0.003)., Discussion: The coadministration of perazine in RIS-medicated patients leads to significantly higher plasma concentrations and C/D values of RIS and its active moiety, and a lower metabolic ratio, reflecting the cytochrome P450 (CYP) 2D6 phenotype. We suggest that the mechanism underlying the effect of perazine on RIS metabolism is based on an inhibition of CYP2D6 and CYP3A4 activity., (© 2017 The British Pharmacological Society.)

Purpose: To disentangle an association between tobacco smoking, smoking habits and pharmacokinetic patterns such as plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM, (RIS+9-OH-RIS) in a naturalistic sample., Methods: Plasma concentrations, dose adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between smokers (n=401) and non-smokers (n=292)., Results: Daily dosage of risperidone differed significantly with smokers receiving higher doses than patients in the control group (p=0.001). No differences were detected in plasma concentrations of the active moiety, RIS and 9-OH-RIS (p=0.8 for AM, p=0.646 for RIS and p=0.538 for 9-OH-RIS). However, dose corrected concentrations (C/D) of metabolite (C/D 9-OH-RIS) and active moiety (C/D AM) differed between significantly between groups (p=0.002 and p=0.007). After stratifying smokers to a group of moderate smokers (<20cigarettes/day) (RS1, n=109) and a group of heavy smokers (≥20cigarettes/day) (RS2, n=135), the comparison between non-smokers and both groups only showed lower values of C/D for 9-OH-RIS (p=0.011) for the group of moderate smokers while other pharmacokinetic parameters did not differ., Conclusions: Apart from the well-known induction of CYP1A2 activity by polycyclic aromatic hydrocarbons, smoking might exert an effect on other CYP isoenzymes as well. A possible interpretation proposes a slight inducing effect of smoking on risperidone metabolism most likely via CYP3A4., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: To investigate in vivo the effect of low-potency antipsychotics on metabolism of risperidone (RIS)., Methods: A therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-OH-RIS of 1584 patients was analyzed. Five groups were compared; a risperidone group (n=842) and four co- medication groups; a group co-medicated with chlorprothixene (n=67), a group with levomepromazine (n=32), a group with melperone (n=46), a group with pipamperone (n=63) and a group with prothipendyl (n=24). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and active moiety (RIS+9-OH-RIS; AM) as well as the metabolic ratios (9-OH-RIS/RIS; MR) were computed., Results: Differences in plasma concentrations were detected for AM and RIS. Pairwise comparisons revealed significant findings; RIS plasma concentrations were higher in co-medication groups than in monotherapy group. Chlorprothixene- and prothipendyl- medicated patients demonstrated no other differences. In the levomepromazine and melperone group plasma and C/D concentrations of AM and RIS were higher, while MRs were lower. For pipamperone, differences included higher C/D values of RIS and lower MRs., Conclusions: Alterations of risperidone metabolism suggest pharmacokinetic interactions for levomepromazine and melperone. In the pipamperone-group, lower MRs as well as higher plasma and C/D levels of RIS suggest potential interactions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The purpose of this study was to disentangle an association between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM (RIS + 9-OH-RIS), and clinical response in a naturalistic sample. Plasma concentrations of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between responders (n = 64) and non-responders (n = 526) using the Clinical Global Impressions (CGI) Scale. Daily dosage of risperidone did not differ between responders and non-responders. Differences for active moiety plasma levels between the two groups did not reach statistical significance. However, responders showed lower plasma concentrations of the parent compound RIS as well as lower metabolic ratios RIS/9-OH-RIS than non-responders (p = 0.017 and p = 0.034). These differences did not remain after controlling for age and baseline symptoms. Furthermore, the cohort was split into two subgroups based on the daily dosage: patients under high (≥6 mg/day) (R H , n = 187) and patients under lower dosages (<6 mg) (R L , n = 403) of risperidone. Differences between responders and non-responders after controlling for demographic and clinical characteristics remained only for plasma concentrations of active moiety in the lower-dose medicated groups; non-responders showed higher active moiety plasma concentrations than responders. Understanding the mechanisms involved and factors associated with the clinical response in patients medicated with antipsychotics is of great interest. Our data imply that clinical response to an antipsychotic treatment cannot be attributed to a single pharmacokinetic pattern. It seems to be rather a complex patchwork of influencing factors such as demographic and clinical characteristics as well as the metabolizer status as surrogate of CYP activity. It seems that the ratio between RIS and 9-OH-RIS may play a crucial role in mediating the clinical effect.

Background: Many indications are discussed for vitamin D substitution, such as osteoporosis, autoimmune diseases, cancer and psychiatric diseases. Also discussed is the fact that the majority of the German population suffer from a vitamin D deficiency., Objective: Review of the study results for these individual diseases and a critical analysis of the currently established therapeutic reference range, which defines a vitamin D deficiency., Material and Methods: A literature search was carried out in the statements of the German Society for Nutrition, in scientific publications and journals., Results: The study results on prevention and therapy of various diseases with vitamin D show inconsistent results. Well-established indications are the prevention of rickets in babies and the supportive therapy for osteoporosis. The currently established reference range for the definition of a vitamin D deficiency came from studies where vitamin D deficiency was correlated to an increase in parathyroid hormone. Different laboratories use different methods for measurement of vitamin D levels., Conclusion: More studies are needed to clarify the role of vitamin D in the prevention and treatment of various diseases. Another problem is that different laboratories do not use the same measurement methods to determine vitamin D and the use of different methods leads to widely varying results which cannot be compared. Therefore, a standardization of the methods would be desirable.

Background: Direct oral anticoagulants currently have no indication for monitoring even though there are data that imply that individual dosing can improve and add safety to the therapy., Methods: An ultra-high performance liquid chromatography method with ultra violet detection has been developed and validated for apixaban, dabigatran, dabigatran etexilate, and rivaroxaban. Protein precipitation with methanol (1:3 vol/vol) was used as sample preparation. Analyses were performed on an Agilent 1290 ultra-high performance liquid chromatography system with an Agilent Poroshell 120 EC-C18-RP column using eluents [A] H2O and [B] methanol with 0.1% formic acid added to each. A gradient run was performed with a flow of 0.7 mL/min at 35°C. Apixaban was detected at 280 nm, dabigatran at 294 nm, dabigatran etexilate at 340 nm, and rivaroxaban at 249 nm., Results: Retention times were 1.83 minutes for dabigatran, 4.10 minutes for rivaroxaban, 4.30 minutes for apixaban, and 6.10 minutes for dabigatran etexilate within a total run time of 7 minutes. Linearity was given over a range from 20 to 300 ng/mL with r >0.999. The limit of detection ranged from 4 to 5 ng/mL and the limit of quantification from 15 to 19 ng/mL, respectively. Usability in daily routine was demonstrated in 27 samples from patients receiving rivaroxaban and 11 samples from patients receiving apixaban. In the absence of validated therapeutic ranges, we estimated "assumed therapeutically effective concentrations" from dose-related ranges for the respective licensed dosages., Conclusions: The method offers a fast, reliable, and low-cost way to quantify direct oral anticoagulants in daily routine even in smaller laboratories without access to liquid chromatography-mass spectrometry.