title: Risperidone-induced extrapyramidal side effects: is the need for anticholinergics the consequence of high plasma concentrations?
abstract: 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.
authors.affiliation: aDepartment of Psychiatry, Psychotherapy and Psychosomatics, and JARA - Translational Brain Medicine, RWTH Aachen University, Aachen bClinical Pharmacology, Departments of Psychiatry and Psychotherapy, and Pharmacology and Toxicology, University of Regensburg, Regensburg cDepartment of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany dSchool for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands eUniversity Hospital of Psychiatry, Bern, Switzerland.
authors.forename: Georgios
authors.initials: G
authors.lastname: Schoretsanitis
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Haen
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
authors.forename: Benedikt
authors.initials: B
authors.lastname: Stegmann
authors.forename: Koen R J
authors.initials: KR
authors.lastname: Schruers
authors.forename: Tanja
authors.initials: T
authors.lastname: Veselinovic
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lammertz
authors.forename: Michael
authors.initials: M
authors.lastname: Paulzen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000097:blood*; D001480:Basal Ganglia Diseases / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D018680:Cholinergic Antagonists / Q000627:therapeutic use*; D016208:Databases, Factual; D004409:Dyskinesia, Drug-Induced / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018967:Risperidone / Q000009:adverse effects* / Q000097:blood*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D018680:Cholinergic Antagonists; D018967:Risperidone