[Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP]. / Therapeutisches Drug-Monitoring in der Neuropsychopharmakologie : Zusammenfassung der Konsensusleitlinien 2017 der TDM-Arbeitsgruppe der AGNP.

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.

Cytochrome P450-mediated interaction between perazine and risperidone: implications for antipsychotic polypharmacy.

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.

Clinical response in a risperidone-medicated naturalistic sample: patients' characteristics and dose-dependent pharmacokinetic patterns.

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.

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment.

BACKGROUND: The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. The objective of the study was to identify pharmacokinetic interactions of different mood stabilizers on the metabolism of risperidone (RIS) under natural conditions. METHODS: A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1,584 adult patients was analyzed. Four groups (n = 1,072) were compared: a control group without a potentially cytochrome interacting comedication (R0, n = 852), a group comedicated with valproate (VPA) (RVPA, n = 153), a group comedicated with lamotrigine (LMT) (RLMT, n = 46), and a group under concomitant medication with carbamazepine (CBZ) (RCBZ, n = 21). Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS and active moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS) were computed. RESULTS: Groups did not differ with regard to the daily dosage (P = 0.46). Differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS and AM (P = 0.003, P < 0.001 and P < 0.001, respectively). Differences remained significant after conducting a Bonferroni correction (P = 0.0125). Pairwise comparisons of the concomitant medication groups with the control group revealed significant differences; RIS C/D ratios were significantly higher in the VPA and the LMT group than in the control group (P = 0.013; P = 0.021). However, these differences did not remain significant after Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS (P < 0.001) as well as the AM (P < 0.001) than the control group; this difference survived the Bonferroni correction. CONCLUSIONS: The data give evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AM when compared with the control group. In case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical significance were found.

Quantification of Methylphenidate, Dexamphetamine, and Atomoxetine in Human Serum and Oral Fluid by HPLC With Fluorescence Detection.

BACKGROUND: For psychostimulants, a marked individual variability in the dose-response relationship and large differences in plasma concentrations after similar doses are known. Therefore, optimizing the efficacy of these drugs is at present the most promising way to exploit their full pharmacological potential. Moreover, it seems important to examine oral fluid as less invasive biological matrix for its benefit in therapeutic drug monitoring for patients with hyperkinetic disorder. METHODS: A high-performance liquid chromatography method for quantification of methylphenidate (MPH), dexamphetamine (DXA), and atomoxetine in serum and oral fluid has been developed and validated. The analytical procedure involves liquid-liquid extraction, derivatization with 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride as a label and chromatographic separation on a Phenomenex Gemini-NX C18 analytical column using gradient elution with water-acetonitrile. The derivatized analytes were detected at 330 nm (excitation wavelength) and 440 nm (emission wavelength). To examine the oral fluid/serum ratios, oral fluid samples were collected simultaneously to blood samples from patients with hyperkinetic disorder. RESULTS: The method allows quantification of all analytes in serum and oral fluid within 16 minutes under the same or similar conditions. Oral fluid/serum ratios for MPH and DXA were highly variable and showed an accumulation of these drugs in oral fluid. CONCLUSIONS: The developed method covers the determination of MPH, DXA, and atomoxetine concentrations in serum and oral fluid after the intake of therapeutic doses. Oral fluid samples are useful for the qualitative detection of MPH and DXA.

Pharmacokinetic patterns of risperidone-associated adverse drug reactions.

PURPOSE: The aim of the study was to investigate a correlation between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety (AM) (RIS + 9-OH-RIS), and adverse drug reactions (ADRs) in a naturalistic sample. METHODS: Plasma concentrations of RIS, 9-OH-RIS, and AM in patients out of a therapeutic drug monitoring (TDM) database complaining ADRs were categorized according to the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 97) and compared to patients without ADRs (n = 398). RESULTS: Patients in the ADR group received a significantly lower daily dosage of risperidone (trimmed mean 3.64 mg/day) than patients without ADRs (4.40 mg/day). No differences were found for active moiety plasma concentrations between the groups (p = 0.454). Differences were detected only in the case of dose-adjusted plasma concentration values (concentration-by-dose, C/D) for 9-OH-RIS, being higher in patients reporting ADRs (4.78 ng/mL/mg) than in patients without ADRs (4.3 ng/mL/mg) (p = 0.037 for Mann-Whitney U test). Note that differences for non-adjusted 9-OH-RIS plasma levels between groups failed to reach significance (p = 0.697). CONCLUSIONS: Our findings are consistent with previous data supporting a prominent role of 9-hydroxyrisperidone, but not of risperidone with regard to ADRs. When studying the various subgroups of reported ADRs separately, the size of these subsamples offers some plausible limitations by reducing the power of the analysis.

[Hyperkinetic disorders in childhood and adolescence- an analysis of KinderAGATE 2009-2012]. / Hyperkinetische störungen im kindes- und jugendalter: eine auswertung der KinderAGATE datenbanken 2009-2012.

OBJECTIVE: This contribution evaluates the prevalence, medication use as well as age and sex distribution in inpatients with hyperkinetic disorders at the KinderAGATE hospitals for 2009-2012. METHOD: The age, sex, leading diagnosis, prescribed medication, and dosage of each patient were recorded anonymously twice a year. They provide an outstanding epidemiological basis for the observation of the actual situation in child and adolescent psychiatry. RESULTS: Compared to our patient collective, patients diagnosed with hyperkinetic disorders (25.5% Pat) were on average 2 years younger and received psychopharmacological treatment more often (statistically significant). Although male patients are dominant here (84.3% HPat, mean age 9.9 years vs. 15.7% HPat, 10.1 years), the same proportion of female and male patients received psychostimulant treatment (48.0% vs. 52.2%). Besides methylphenidate, amphetamine, and atomoxetine, the antipsychotics risperidone, pipamperone, and quetiapine were noticeably often prescribed. CONCLUSION: Methylphenidate remains the drug of first choice in the treatment of ADHD. There is an upward trend in the proportion of patients being treated with antipsychotics, though this is not statistically significant. Because of the discrepancy between the available evidence and prescription practice in child and adolescent psychiatry, there is still a great demand for studies regarding long-term efficacy and side effects.

[Depressive disorders in childhood and adolescence - an analysis of KinderAGATE 2010]. / Depressive störungen im kindes- und jugendalter.

OBJECTIVE: The present analysis evaluates the prevalence and medication use in inpatients with depression during childhood and adolescence at the KinderAGATE hospitals in 2010. Also discussed are age and sex distribution. METHOD: Since 2009 the following information has been recorded anonymously twice a year from each patient at the participating hospitals of KinderAGATE: age, sex, leading diagnosis, prescribed medication and dosage. The data obtained provide an excellent epidemiological basis for the observation of the prescription practice in child and adolescent psychiatry. RESULTS: In 2010, 8.4 % of the patients included were treated for a depressive disorder at the KinderAGATE hospitals. This is only a small portion compared to the rates found in adult psychiatry (25.8 % of patients). In our sample male patients diagnosed with depression (58 % DPat, mean age 13.8 years) were treated more often and earlier than female patients (42 % DPat, mean age 15.3 years). Fluoxetine and mirtazapine were the most frequently prescribed substances. Sertraline, escitalopram, and citalopram were also prescribed. CONCLUSION: A reserved medical treatment can be observed in child and adolescence psychiatry. Off-label use seems to be nearly unavoidable due to the lack of newly authorized medicine. Moreover, the numerous prescriptions for fluoxetine, the only SSRI currently approved for this age group in Germany, lead to the question of possible unauthorized alternatives.

Pharmacokinetics of risperidone in different application forms - Comparing long-acting injectable and oral formulations.

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.

Effects of the Proton Pump Inhibitors Omeprazole and Pantoprazole on the Cytochrome P450-Mediated Metabolism of Venlafaxine.

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.

TDM in psychiatry and neurology: A comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians.

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.

Effect of smoking on risperidone pharmacokinetics - A multifactorial approach to better predict the influence on drug metabolism.

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.

Pharmacokinetic considerations in antipsychotic augmentation strategies: How to combine risperidone with low-potency antipsychotics.

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.

Body mass index (BMI) but not body weight is associated with changes in the metabolism of risperidone; A pharmacokinetics-based hypothesis.

OBJECTIVE: We sought to unravel the influence of body weight and body mass index (BMI), both consistently reported as pharmacokinetic relevant parameters, on metabolism of risperidone in a naturalistic sample. METHODS: Conducting non parametrical tests we sought for correlations between plasma concentrations of RIS, 9-OH-RIS and AM and body weight and BMI in patients out of a therapeutic drug monitoring (TDM) database. Further, we stratified patients to three groups based upon BMI values and compared drug concentrations between groups. RESULTS: Although body weight failed to correlate with pharmacokinetic parameters, BMI was positively correlated with plasma concentrations of the active metabolite (9-OH-RIS) (rs=0.121, p=0.002) and active moiety (sum of RIS+9-OH-RIS) (rs=0.128, p=0.001) as well as dose adjusted plasma concentrations of the active moiety (rs=0.08, p=0.04). The comparison of pharmacokinetic parameters between different BMI groups yielded lower plasma concentrations of 9-OH-RIS in patients with low BMI (<20kg/m2) and higher plasma concentrations of the active moiety in obese patients (BMI ≥30kg/m2) when compared with the control group (30>BMI≥20kg/m2). By comparing low vs. high BMI patients, the latter group showed higher 9-OH-RIS plasma concentrations. CONCLUSIONS AND LIMITATIONS: Considerable alterations in metabolism of risperidone were detected when comparing obese and cachectic patients with the control group in alignment with the positive correlation between BMI values and plasma concentrations of the active metabolite and active moiety as well as dose adjusted plasma concentrations of the active moiety. We suggest changes in CYP2D6 or CYP3A4 activity or differences in P-glycoprotein function in obese patients with greater BMI as a plausible mechanism underlying these alterations.

Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients - thinking of clinically relevant CYP2D6 interactions.

BACKGROUND: Treatment of arterial hypertension in patients with severe mental illnesses often results in polypharmacy, potentially leading to drug-drug interactions. The objective of the study was to analyse the in vivo inhibitory potential of two antihypertensive drugs, amlodipine and metoprolol on CYP2D6 catalysed 9-hydroxylation of risperidone (RIS). METHODS: A therapeutic drug monitoring database with plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) of 1584 patients was analysed. Three groups were considered; a group of patients receiving RIS without a potentially cytochrome influencing co-medication (control group, R0, n=852), a group co-medicated with amlodipine (RA, n=27) and a group, co-medicated with metoprolol (RM, n=41). Plasma concentrations, concentration-to-dose ratios (C/Ds) of RIS, 9-OH-RIS and the active moiety (AM), as well as the metabolic ratios were computed and compared using the Kruskal-Wallis test, the Mann-Whitney U test and the Jonckheere-Terpstra test to determine the means and different patterns of distribution of plasma concentrations as well as the concentration-to-dose ratios. RESULTS: The median daily dosage of RIS did not differ between the groups (p=0.708). No differences were found in median plasma concentrations of RIS, 9-OH-RIS and AM. However, concentration-to-dose ratios for RIS, 9-OH-RIS and AM were significantly higher in the amlodipine group (p=0.025, p=0.048 and p=0.005). In the metoprolol group, the concentration-to-dose ratio for RIS was significantly higher than in the control group (p=0.017), while the C/D for 9-OH-RIS and AM was not. CONCLUSIONS AND LIMITATIONS: Our data show a potential pharmacokinetic interaction, most likely via CYP3A4 between amlodipine and RIS, reflected in significantly different C/Ds for RIS, 9-OH-RIS and AM. Although the interaction did not result in significantly higher plasma levels, changes in C/Ds and their distribution with regard to the median concentrations were observed.

Risperidone-induced extrapyramidal side effects: is the need for anticholinergics the consequence of high plasma concentrations?

Antipsychotic drugs can induce various undesirable adverse motor reactions, such as extrapyramidal side effects (EPS). A widely accepted pharmacodynamic mechanism underlying EPS includes an increase in striatal D2-receptor occupancy. However, less is known about the pharmacokinetic background of EPS. The aim of this study was to analyze in-vivo possible pharmacokinetic patterns underlying biperiden-treated EPS in risperidone (RIS)-medicated patients. A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone (9-OH-RIS) of 2293 adult inpatients and outpatients was analyzed. Two groups were compared: a group receiving RIS (n=772) and a group comedicated with biperiden (n=68). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS, and active moiety (AM) (RIS+9-OH-RIS) as well as ratios of concentrations for metabolite to parent drug (9-OH-RIS/RIS) were computed. We compared the plasma concentrations of the different compounds between the two groups considering the prescription of biperiden as an indirect report of EPS. The daily dosage of RIS did not differ between groups. No differences were detected in case of plasma concentrations and C/D of RIS and active metabolite between the groups. However, plasma concentrations of the AM were significantly higher in the comedicated group (P=0.032) and showed a trend in terms of the active metabolite 9-OH-RIS (P=0.053). Data indicate enhanced AM plasma concentrations of RIS in patients comedicated with biperiden as an EPS treatment. This might underscore an association between higher plasma concentrations of the AM and treatment-requiring EPS.