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

Nazar Kuzo, Ekkehard Haen, Dominic M. Ho, Hiroyoshi Takeuchi, Marianna Piras, Chin Bin Eap, Renato de Filippis, Philipp Homan, John M. Kane, Marc André Roy, Michael Paulzen, Georgios Schoretsanitis

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish
Pages (from-to)1567-1578
Number of pages12
JournalEuropean Archives of Psychiatry and Clinical Neuroscience
Issue number7
StatePublished - Oct 2023
Externally publishedYes


  • Antipsychotics
  • Clozapine
  • Divided dosing
  • Polypharmacy
  • Treatment-resistant schizophrenia


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