Therapeutic Reference Range for Clozapine Plasma Levels in
                    Parkinson’s Disease or Dementia: A Systematic Review and Individual Participant
                    Data Meta-analysis

Nazar Kuzo; Marianna Piras; Ulrich C. Lutz; Ekkehard Haen; Chin B. Eap; Christoph Hiemke; Michael Paulzen; Georgios Schoretsanitis

doi:10.1055/a-2560-4028

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry
DOI: 10.1055/a-2560-4028

Original Paper

Therapeutic Reference Range for Clozapine Plasma Levels in Parkinson’s Disease or Dementia: A Systematic Review and Individual Participant Data Meta-analysis

Nazar Kuzo

¹Department of Adult Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, Switzerland

,

Marianna Piras

²Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Switzerland

,

Ulrich C. Lutz

³Department of Addiction Therapy and Withdrawal, Clinic Schloß Winnenden, Germany

⁴University Hospital of Psychiatry and Psychotherapy, Tübingen, Germany

,

Ekkehard Haen

⁵Department of Psychiatry and Psychotherapy, Clinical Pharmacology, University of Regensburg, Germany

⁶Department of Pharmacology and Toxicology, University of Regensburg, Germany

⁷Clinical Pharmacology, Institute AGATE gGmbH, Pentling, Germany

,

Chin B. Eap

²Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Switzerland

⁸School of Pharmaceutical Sciences, University of Geneva, Switzerland

⁹Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital, Switzerland

¹⁰Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Switzerland

,

Christoph Hiemke

¹¹Department of Psychiatry and Psychotherapy, University Medical Center of Mainz, Germany

¹²Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Germany

,

Michael Paulzen

¹³Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA – Translational Brain Medicine, Aachen, Germany

¹⁴Alexianer Center for Mental Health Aachen, Aachen, Germany

,

Georgios Schoretsanitis

¹Department of Adult Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, Switzerland

¹⁵The Zucker Hillside Hospital, Department of Psychiatry Research, Northwell Health, Glen Oaks, New York, USA

¹⁶Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA

› Author Affiliations

Abstract

Introduction

Clozapine is a recommended treatment for psychotic symptoms in patients with Parkinson’s disease (PD) and/or dementia. However, the therapeutic reference range for clozapine in these patients has not been established hitherto.

Materials and Methods

The study was performed in three university hospitals in Germany and Switzerland, including clozapine-treated patients with PD and/or dementia. The primary outcome was tolerability based on reports of adverse drug reactions and/or changes in laboratory tests or electrocardiogram and/or clozapine discontinuation. We meta-analyzed demographic and pharmacokinetic parameters in patients tolerating clozapine well versus not. A meta-analytic summary receiver operating characteristic (SROC) to establish the clozapine upper level associated with poor tolerability was estimated.

Results

We analyzed a total of 99 patients suffering from PD (56.6%) and/or dementia (49.5%) with a mean age of 70.3±9.5 years and 41.4% females; poor tolerability was reported in 26 of 99 patients (26.3%). When comparing patients with and without poor tolerability, there were no differences in age, body mass index, sex, smoking, or clozapine dose, nor did we find statistically significant differences in clozapine levels (standardized mean difference 0.46, 95% confidence interval − 0.04 to 0.96, p=0.07), and heterogeneity was low (I²=0.0%). Clozapine blood levels above 193 ng/mL were associated with poor tolerability (SROC area-under-curve 0.6, sensitivity 39.7%, specificity 79.9%).

Conclusion

One of four patients with PD and/or dementia treated with clozapine did not tolerate clozapine well, which was associated with a trend toward elevated clozapine concentrations. Monitoring drug levels may help to improve tolerability in these patients.

Keywords

therapeutic drug monitoring - clozapine - Parkinson’s disease - dementia

Full Text

References

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Supplementary Material

Supplementary Material