Clozapine, an atypical antipsychotic, remains the sole medication with demonstrated efficacy in reducing both symptoms and relapse risk in adults with treatment resistant schizophrenia (NICE, 2015). Its use involves strict mandatory blood monitoring due to the risk of agranulocytosis, an acute drop in circulating granulocytes that leaves the person with very limited ability to fight infections. In the UK, patients are required to register with a clozapine monitoring service and full blood counts must be monitored at least weekly for the first 18 weeks, at least fortnightly between weeks 18 to 52, and at least four weekly after one year of treatment with stable full blood count.
In the United States, the Food and Drug Administration removed its mandatory Risk Evaluation and Mitigation Strategy programme for clozapine in 2025, although blood monitoring is still recommended. In the UK, blood monitoring rules remain in place, but the Medicines and Healthcare products Regulatory Agency launched a review of its requirements in 2025. Interest in less frequent testing grew during the COVID-19 pandemic, when some NHS trusts temporarily moved low-risk patients to 12-weekly blood tests to reduce infection risk. A small London study of this change found no cases of agranulocytosis over one year (Oloyede et al., 2023).
This large scale observational study aimed to evaluate the safety of 12-weekly monitoring of neutrophil count in patients taking long-term clozapine (Taylor et al, 2025). Neutrophils are the most abundant type of white blood cell, and they are the immune system’s first responders to infection.
Methods
This was a retrospective, observational study which included all registered patients on the Zaponex Treatment Access System approved for 12-weekly monitoring, registered March 2020 to November 2022, followed up to August 2024. All had a paranoid schizophrenia diagnosis. The patients and study was based in the UK.
The authors gathered data via a clozapine monitoring service without access to patient identifiers and therefore did not require patient consent. As the reduced monitoring was outside the terms of the product license, off-license forms were completed. It was not clear if it was the authors or responsible consultant that completed these forms.
The study complied with the ethical standards of the UK Health Research Authority. Strengthening the Reporting of Observational studies in Epidemiology reporting guidelines were also adhered to. The agreed criteria included patients with no history of neutropenia and good compliance with clozapine treatment for at least a year. Patients with benign ethnic neutropenia (BEN: a congenital form of low neutrophil counts and most prevalent in people of African, Middle Eastern and West Indian ancestry) were included.
Outcomes of interest included death from clozapine induced agranulocytosis and development of adverse blood results during follow-up. Patients were followed-up until discontinuation of clozapine, loss to follow-up due to death, or until the end of the study period in 2024.
Results
A total of 1,025 clozapine patients with a paranoid schizophrenia diagnosis were monitored at 12-weekly intervals. There was a variety of ethnicities including White, Black, Asian and mixed. Overall there were more males (69%) than females (31%) in this cohort study with a mean age of 47 years old. The median follow-up time per participant was 4 years.
- 9 patients had a red result, this means their white cell count was less than 3.0 x10⁹/L and/or their neutrophil counts was less than 1.5 x10⁹/L.
- 34 patients had an amber result which means their white cell count was between 3.0 x10⁹/L to 3.5 x10⁹/L and/or their neutrophil counts was between 1.5 x10⁹/L to 2.0 x10⁹/L.
A red result is more serious than an amber result. Blood parameters for green, amber, red results for BEN patients are different compared to standard patients due to their chronically lower neutrophil counts. BEN patients’ blood parameters are determined by consultant haematologists. There were no cases of agranulocytosis recorded. Due to this, 83% patients continued on reduced frequency blood monitoring for the rest of the study, 2% stopped and 15% temporarily interrupted reduced monitoring but restarted before the end of the follow-up period.
Eleven patients (1%) were lost to follow-up. During the study, 42 patients (4%) died. Respiratory disease was by far the most common cause of death (22 deaths), followed by cardiovascular disease (9). The cause was unknown for another 9 deaths. Other causes were substance misuse (3), cancer (3), diabetes (2), seizure (1) and bowel obstruction (1), and one death was recorded as clozapine related. Some deaths had more than one cause recorded. None of the people who died had a red or amber result during 12-weekly monitoring, and no deaths were caused by agranulocytosis.
In summary, there were no cases of agranulocytosis and no deaths from agranulocytosis among long-term patients who moved to 12-weekly monitoring. Most patients (83%) stayed on 12-weekly monitoring for the rest of the study.
In this study, the authors found an increased number of deaths from respiratory disease and used previous studies to note that pneumonia could occur in those who start clozapine treatment and advised to put measures in place to reduce the risk of pneumonia such as the pneumococcal vaccine.
Conclusions
The authors concluded that it was safe to reduce the frequency of clozapine monitoring to 12-weekly in long-term clozapine patients. However, it is important to consider the strengths and limitations of the study before drawing firm conclusions about wholesale changes to monitoring.
Strengths and limitations
This study has several strengths. The research question was clear, and the outcomes (agranulocytosis, deaths from agranulocytosis and abnormal blood results) were the right ones for judging safety. Everyone in the sample had the same diagnosis and treatment. The sample was large: 1,025 patients followed up for a median of four years, or 3,366 person-years in total. Blood results came from laboratory tests recorded by a UK clozapine monitoring service, the Zaponex Treatment Access System, which reduces the risk of measurement bias. The sample was also ethnically diverse (48% White, 30% Black, 11% Asian, 3% mixed and 8% other) and included people with benign ethnic neutropenia. The paper doesn’t say who was in the “other” group.
There are also important limitations.
- First, there was no control group of patients on standard 4-weekly monitoring. This means the study can show that the risk was low on 12-weekly monitoring, but not that 12-weekly monitoring is as safe as 4-weekly.
- Second, the sample was highly selected. Patients had to have taken clozapine reliably for at least a year with no history of neutropenia, and on average they had been taking it for 10 years. The risk of agranulocytosis is highest early in treatment and very low after that. So this was a low-risk group, and the findings may not apply to everyone currently on 4-weekly monitoring.
- Third, agranulocytosis is rare, so even a large study can miss it. The authors cite an expected rate after the first year of 0.31 to 0.52 cases per 1,000 person-years (Schulte, 2006). With no cases in 3,366 person-years, the true rate could still be as high as about 0.9 per 1,000 person-years (the upper 95% confidence limit). So the study cannot rule out a rate at or above the usual background risk.
- Fourth, key details were not reported. The study did not record clozapine dose, smoking status (which affects clozapine levels), other medicines or past medical history. Other medicines matter because some, such as carbimazole, co-trimoxazole, carbamazepine and azathioprine, can also cause agranulocytosis. We also don’t know what happened to the nine patients with a red result, why nine deaths had an unknown cause, or anything about the one death recorded as clozapine related.
- Finally, the data came from only one of the three UK clozapine monitoring services. The results may not reflect patients registered with the other two.
Implications for practice
After the first year of treatment, UK product licences currently require blood tests at least every 4 weeks, as long as neutrophil counts are stable (Viatris, 2026; Leyden Delta BV, 2024). Agranulocytosis is not the only reason to stop clozapine. Other potentially serious blood conditions, such as eosinophilia (a high level of eosinophils, a type of white blood cell) and thrombocytopenia (low platelets), also show up in the full blood count. Any change to monitoring needs to keep these in view.
Clozapine works for people with treatment-resistant schizophrenia. It reduces hospital readmissions and lowers suicide risk (Fernandez-Egea et al., 2024), yet it remains underused. Frequent blood tests are one reason: they are a burden, and they can lead people to stop treatment or disengage from care.
This study adds to the evidence that 12-weekly monitoring may be reasonable for some people who have taken clozapine for a long time and have stable blood counts. There were no cases of agranulocytosis and no deaths from it. But this is a single observational study with no control group and a low-risk sample, so on its own it is not enough to change practice for everyone.
The deaths in this study also point to a different risk. Respiratory disease was the most common cause of death, and no deaths were due to agranulocytosis. As the authors note, pneumonia may matter more for clozapine safety than agranulocytosis. Measures such as the pneumococcal vaccine, and quick treatment of chest infections, deserve as much attention as the blood test schedule.
Blood tests are often a regular point of contact with services. For people who live alone or have little support, fewer tests could mean fewer chances to spot problems early or to ask for help. On the other hand, frequent tests can feel like a burden and may push some people away from care. If blood tests become less frequent, other contact with the care team should carry on, so that fewer tests don’t mean less support.
With fewer blood tests, people will rely more on spotting and reporting the signs of agranulocytosis themselves. These include fever, chills, flu-like symptoms, a sore throat or mouth sores, extreme tiredness, and weakness caused by a drop in blood pressure. Clear information and good conversations about clozapine and its side effects are essential. This may be harder for older adults and for people with cognitive impairment or impaired decision-making capacity, who may find it difficult to recognise or communicate new symptoms. They may need extra support from family, carers or staff.
More research is needed before guidelines change. Studies that compare 12-weekly with 4-weekly monitoring, and systematic reviews that bring the growing evidence together, would help. Any change to practice would also need agreement from the clozapine monitoring services and changes to the product licences.
Statements of interest
WingYee declares no conflicts of interest and AI was not used in the development of the blog.
Edited by
Dr Simon Bradstreet.
Links
Primary paper
David Taylor, Siobhan Gee, Marinka Helthuis, Ebenezer Oloyede. (2025) The Safety of 12-Weekly Monitoring of Neutrophil Count in Long-Term Clozapine Patients. Acta Psychiatr Scand. 2025 Sep;152(3):187-192.
Other references
National Institute for Health and Care Excellence (2015) Psychosis and schizophrenia in adults. QS80.
Oloyede et al. (2023). Clinical impact of reducing the frequency of clozapine monitoring: controlled mirror-image cohort study. The British Journal of Psychiatry, 223, pp.382-388.
Viatris (2026) Clozaril 25mg Tablets SmPC.
Leyden Delta BV (2024) Zaponex 100mg orodispersible tablets SmPC.
Fernandez-Egea et al. (2024). Mortality associated with clozapine what is the evidence, The British Journal of Psychiatry, 225(3), pp.357-359.