Therapeutic reference range for clozapine plasma levels when prescribed in patients with Parkinson's disease or dementia: a three-center cohort study and meta-analysis

Pharmacopsychiatry

Abstract

Clozapine is a common drug in the treatment of psychotic symptoms in patients with Parkinson’s disease (PD) and dementia. However, the therapeutic reference range for clozapine levels in plasma or serum for PD and dementia has not been established so far. The study was performed in three university hospitals in Germany and Switzerland; each study site was analyzed separately. Patients with PD or dementia treated with clozapine were included. The primary outcome was safety based on reports of adverse drug reactions (ADRs), changes in laboratory test or electrocardiogram, or clozapine discontinuation. We meta-analyzed differences regarding demographic and pharmacokinetic parameters in patients tolerating clozapine well vs. not. A meta-analytic summary receiver operating characteristic (SROC) to establish the clozapine blood level cut-off associated with safety issues was estimated. Safety problems were reported in 26 (26.3%) patients from a total of 99 included. Comparing patients with vs without safety problems, we found no difference regarding age (p=0.3), body mass index (p=0.5), sex (p=0.9), smoking status (p=0.9), or clozapine daily dose (p=0.3). We found a medium-effect trend of increased clozapine blood concentration in patients with safety problems (Standardized mean difference 0.46, 95% confidence interval -0.04 – 0.96, p=0.07). Clozapine blood levels above 193 ng/mL were associated with safety problems (SROC 0.6, sensitivity 39.7%, specificity 79.9%). One out of four patients with PD or dementia treated with clozapine did not tolerate clozapine well. Therapeutic drug monitoring may be used to predict tolerance problems in these patients. Publication History Article published online: 12 March 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

Authors 8

1. Nazar Kuzo

   University of Zurich · Psychiatrische Universitätsklinik Zürich

   Affiliation as printed

   Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland

2. Marianna Piras

   Centre Hospitalier Universitaire Vaudois · University of Lausanne

   Affiliation as printed

   Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

3. Ulrich C. Lutz

   Rems-Murr-Klinikum

   Affiliation as printed

   Department of Addiction Therapy and Withdrawal, Clinic Schloß Winnenden, Winnenden, Germany

4. Ekkehard Haen

   University of Regensburg

   Affiliation as printed

   Clinical Pharmacology, Institute AGATE gGmbH, Pentling, Germany

   Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany

   Department of Psychiatry and Psychotherapy, Clinical Pharmacology, University of Regensburg, Regensburg, Germany

5. Chin B. Eap

   University of Geneva · Centre Hospitalier Universitaire Vaudois · University of Lausanne

   Affiliation as printed

   Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

   Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva, Switzerland

   School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

   Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

6. Christoph Hiemke

   University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Department of Psychiatry and Psychotherapy, University Medical Center of Mainz, Mainz, Germany

   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany

7. Michael Paulzen Aachen Department of Psychiatry, Psychotherapy and Psychosomatics

   RWTH Aachen University

   Affiliation as printed

   Alexianer Hospital Aachen, Aachen, Germany

   Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA – Translational Brain Medicine, Aachen, Germany

8. Georgios Schoretsanitis

   Northwell Health · University of Zurich · Donald & Barbara Zucker School of Medicine at Hofstra/Northwell · Zucker Hillside Hospital · Psychiatrische Universitätsklinik Zürich

   Affiliation as printed

   Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland

   Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA

   The Zucker Hillside Hospital, Department of Psychiatry Research, Northwell Health, Glen Oaks, New York, USA