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

Abstract

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.

Comparison of the Effectiveness and Safety of Clozapine Between Once-Daily and Divided Dosing Regimen in Patients With Treatment-Resistant Schizophrenia

“…These factors may be associated with the dosing regimen of clozapine. Kuzo et al 9 found that divided dosing led to more severe clinical symptoms and a higher clozapine dose than once-daily dosing. Also, based on the chart review, some data may be incomplete, such as adverse effects and reasons for clozapine discontinuation.…”

“…8 However, dosing regimens of clozapine differ between countries. In a 2-center cross-sectional study in Germany and Switzerland, Kuzo et al 9 found that once-daily dosing of clozapine was prescribed in 25.2% to 32.3% of cases, whereas in a study in the United States and Canada, Takeuchi et al 10 found that once-daily dosing of clozapine was commonly prescribed in approximately 75% of cases. In addition, a cross-sectional study comparing the actual plasma concentration of clozapine achieved by once-daily and divided dosing regimens in patients with schizophrenia or schizoaffective disorders found no difference in psychotic symptom resolution, adverse effects, or peak/trough plasma concentration between once-daily and divided dosing regimens.…”

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

“… 190 , 234 , 378 Importantly, recent findings indicate that clozapine administration partly during daytime may not reduce the burden of sedation. 379 Emphasizing nocturnal administration whenever possible while taking into account individual preferences appears to be more promising also given that complex dosing instructions might be too demanding for some patients. 379 Adding aripiprazole constitutes another option.…”

“… 379 Emphasizing nocturnal administration whenever possible while taking into account individual preferences appears to be more promising also given that complex dosing instructions might be too demanding for some patients. 379 Adding aripiprazole constitutes another option. 88 , 378 Augmentation with modafinil has also been discussed, but findings from a placebo-controlled pilot trial were not generally supportive.…”

Once‐ versus multiple‐daily dosing of clozapine

“…Investigators recently conducted a comparative study of patients from two psychiatric hospitals in two European hospital networks who were treated with one of the two clozapine dosing regimens. They also performed a systematic review and meta‐analysis of studies, with the aim of addressing potential differences in safety and effectiveness between the dosing regimens (Kuzo et al 2022).…”