Discovering interactions in polypharmacy: Impact of metamizole on the metabolism of quetiapine.

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, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 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.

Assessing Pharmacokinetic Correlates of Escitalopram-Related Adverse Drug Reactions.

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.

Pharmacokinetic correlates of clinical response in a naturalistic sample of escitalopram-treated patients.

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.

Discovering interactions in augmentation strategies: Impact of duloxetine on the metabolism of aripiprazole.

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.

Lower sertraline plasma concentration in patients co-medicated with clozapine-Implications for pharmacological augmentation strategies in schizophrenia.

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.

Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis.

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.

[Drug-drug interactions-How can we protect ourselves from the flood of information?] / Arzneimittelwechselwirkungen ­ wie kann man sich vor der Informationsflut schützen?

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.

Simultaneous Quantification of 11 Antiseizure Medications and Metabolites in Serum for Therapeutic Drug Monitoring Using High-Performance Liquid Chromatography with Ultraviolet Detection: A Short Communication.

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.

Dose-Related Reference Range as a Tool in Therapeutic Drug Monitoring.

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).

[Adverse Drug Reactions in Geriatric Psychiatric Patients - Influence of Potentially Inappropriate Drugs]. / Unerwünschte Arzneimittelwirkungen in der Gerontopsychiatrie.

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.

Effects of body weight, smoking status, and sex on plasma concentrations of once-monthly paliperidone palmitate.

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.

Pharmacokinetic Correlates of Once-Monthly Paliperidone Palmitate-Related Adverse Drug Reactions.

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.

Clinical response in patients treated with once-monthly paliperidone palmitate: analysis of a therapeutic drug monitoring (TDM) database.

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 (χ2) 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.

Asymmetric dimethylarginine in psychiatric disorders.

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.

Body mass index as a determinant of clozapine plasma concentrations: A pharmacokinetic-based hypothesis.

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 (CLZ0, 20-30 kg/m2, n=266), a group with high body mass index (CLZhigh, body mass index ⩾30 kg/m2, n=162) and with low body mass index values (CLZlow, body mass index <20 kg/m2, n=27). Comparisons of plasma and dose-adjusted plasma concentrations (C/D) of clozapine were based on the Spearman's correlation (rs), Kruskal Wallis and Mann-Whitney-U tests. For percentages we used the Pearson chi-square test (χ2). 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 CLZlow and CLZhigh compared to CLZ0 (p=0.001 for χ2 test). Plasma and C/D values were positively associated with body mass index (rs=0.108, p=0.022 and rs=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 CLZhigh compared to CLZ0 (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.

Elevated Clozapine Concentrations in Clozapine-Treated Patients with Hypersalivation.

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.

[Antihypertensive drugs in psychiatry : Prescription behavior and potential drug-drug interactions]. / Antihypertensiva in der Psychiatrie : Verordnungsverhalten und Interaktionspotenzial.

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.

Metamizole but not ibuprofen reduces the plasma concentration of sertraline: Implications for the concurrent treatment of pain and depression/anxiety disorders.

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.

Lack of Smoking Effects on Pharmacokinetics of Oral Paliperidone-analysis of a Naturalistic Therapeutic Drug Monitoring Sample.

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 χ2, 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.