Pinioti, Elisavet, Glarou, Eleni  ORCID: https://orcid.org/0000-0001-5666-2458, Lappas, Andreas S., Fober, Iwo, Helfer, Bartosz, Siafis, Spyridon, Christodoulou, Nikos, Nikolakopoulou, Adriani, Leucht, Stefan and Samara, Myrto
2025.
Examining the safety profile of clozapine versus other antipsychotics: systematic review and meta-analysis.
The British Journal of Psychiatry
10.1192/bjp.2025.10421
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Abstract
Background Antipsychotics are first-line treatments for schizophrenia, yet many patients show inadequate response. Clozapine, the gold standard for treatment-resistant schizophrenia, remains underutilised due to safety and monitoring concerns. Aims To evaluate the adverse effects of clozapine in schizophrenia through a meta-analysis of randomised controlled trials (RCTs). Method We systematically searched MEDLINE, CENTRAL, Embase, PsycINFO, ClinicalTrials.gov and WHO ICTRP up to 10 October 2024 for RCTs comparing clozapine (as either monotherapy or combination therapy) with other antipsychotics. We assessed 37 distinct adverse outcomes. Risk ratios were calculated for dichotomous outcomes and standardised mean differences for continuous outcomes, with confidence intervals. Results A total of 116 RCTs (n= 8431) were included. In 69 monotherapy RCTs (n= 6281), clozapine showed no difference in either mortality (risk ratio 1.01, 95% CI: 0.50, 2.01, prevalence 0.1%) or discontinuation due to adverse effects (risk ratio 1.18, 95% CI: 0.91, 1.53, prevalence 7.2%). Agranulocytosis risk was nearly tripled (risk ratio 2.81, 95% CI: 0.97, 8.12, prevalence 0.7%), although with wide confidence intervals. Clozapine increased the risk of seizures (risk ratio 3.61, 95% CI: 1.80, 7.95, prevalence 3.1%) and orthostatic hypotension/bradycardia/syncope (risk ratio 1.66, 95% CI: 1.00, 2.77, prevalence 11%). No difference was found for myocarditis/cardiomyopathy (risk ratio 0.33, 95% CI: 0.01, 8.13). Clozapine increased the risk of leukopenia, hypersalivation, sedation, tachycardia, hypertension, constipation, nausea/vomiting, fever, flu-like syndrome and headache. In 47 combination RCTs (n = 2150), clozapine combinations were not associated with increased risk of severe adverse effects; no cases of agranulocytosis (21 RCTs, n = 894) or seizures (8 RCTs, n= 313) were reported in trials that explicitly assessed these outcomes. Conclusions Life-threatening adverse events remain rare with clozapine. With appropriate monitoring, its safety profile supports broader and potentially earlier use. Future studies should refine monitoring protocols and explore additional indications. Keywords Clozapine; adverse effects; agranulocytosis; tolerability;schizophrenia.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Medicine Research Institutes & Centres > Centre for Trials Research (CNTRR) |
| Subjects: | R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica |
| Uncontrolled Keywords: | clozapine; adverse effects; agranulocytosis; tolerability; schizophrenia |
| Publisher: | Cambridge University Press |
| ISSN: | 0007-1250 |
| Date of First Compliant Deposit: | 28 October 2025 |
| Date of Acceptance: | 25 August 2025 |
| Last Modified: | 29 Oct 2025 12:26 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/181942 |
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