Clozapine, an atypical antipsychotic, stays the only treatment with demonstrated efficacy in lowering each signs and relapse danger in adults with remedy resistant schizophrenia (NICE, 2015). Its use includes strict necessary blood monitoring as a result of danger of agranulocytosis, an acute drop in circulating granulocytes that leaves the particular person with very restricted means to combat infections. Within the UK, sufferers are required to register with a clozapine monitoring service and full blood counts have to be monitored no less than weekly for the primary 18 weeks, no less than fortnightly between weeks 18 to 52, and no less than 4 weekly after one yr of remedy with secure full blood depend.
In america, the Meals and Drug Administration eliminated its necessary Threat Analysis and Mitigation Technique programme for clozapine in 2025, though blood monitoring remains to be beneficial. Within the UK, blood monitoring guidelines stay in place, however the Medicines and Healthcare merchandise Regulatory Company launched a evaluate of its necessities in 2025. Curiosity in much less frequent testing grew throughout the COVID-19 pandemic, when some NHS trusts briefly moved low-risk sufferers to 12-weekly blood exams to scale back an infection danger. A small London examine of this variation discovered no instances of agranulocytosis over one yr (Oloyede et al., 2023).
This massive scale observational examine aimed to judge the security of 12-weekly monitoring of neutrophil depend in sufferers taking long-term clozapine (Taylor et al, 2025). Neutrophils are probably the most ample kind of white blood cell, and they’re the immune system’s first responders to an infection.
Strategies
This was a retrospective, observational examine which included all registered sufferers on the Zaponex Therapy Entry System permitted for 12-weekly monitoring, registered March 2020 to November 2022, {followed} as much as August 2024. All had a paranoid schizophrenia analysis. The sufferers and examine was primarily based within the UK.
The authors gathered information by way of a clozapine monitoring service with out entry to affected person identifiers and due to this fact didn’t require affected person consent. Because the decreased monitoring was outdoors the phrases of the product license, off-license types have been accomplished. It was not clear if it was the authors or accountable advisor that accomplished these types.
The examine complied with the moral requirements of the UK Well being Analysis Authority. Strengthening the Reporting of Observational research in Epidemiology reporting tips have been additionally adhered to. The agreed standards included sufferers with no historical past of neutropenia and good compliance with clozapine remedy for no less than a yr. Sufferers with benign ethnic neutropenia (BEN: a congenital type of low neutrophil counts and most prevalent in folks of African, Center Jap and West Indian ancestry) have been included.
Outcomes of curiosity included loss of life from clozapine induced agranulocytosis and improvement of antagonistic blood outcomes throughout follow-up. Sufferers have been followed-up till discontinuation of clozapine, loss to follow-up as a consequence of loss of life, or till the tip of the examine interval in 2024.
Outcomes
A complete of 1,025 clozapine sufferers with a paranoid schizophrenia analysis have been monitored at 12-weekly intervals. There was a wide range of ethnicities together with White, Black, Asian and combined. General there have been extra males (69%) than females (31%) on this cohort examine with a imply age of 47 years previous. The median follow-up time per participant was 4 years.
- 9 sufferers had a purple end result, this implies their white cell depend was lower than 3.0 x10⁹/L and/or their neutrophil counts was lower than 1.5 x10⁹/L.
- 34 sufferers had an amber end result which suggests their white cell depend was between 3.0 x10⁹/L to three.5 x10⁹/L and/or their neutrophil counts was between 1.5 x10⁹/L to 2.0 x10⁹/L.
A purple result’s extra severe than an amber end result. Blood parameters for inexperienced, amber, purple outcomes for BEN sufferers are completely different in comparison with normal sufferers as a consequence of their chronically decrease neutrophil counts. BEN sufferers’ blood parameters are decided by advisor haematologists. There have been no instances of agranulocytosis recorded. Because of this, 83% sufferers continued on decreased frequency blood monitoring for the remainder of the examine, 2% stopped and 15% briefly interrupted decreased monitoring however restarted earlier than the tip of the follow-up interval.
Eleven sufferers (1%) have been misplaced to follow-up. Throughout the examine, 42 sufferers (4%) died. Respiratory illness was by far the most typical reason behind loss of life (22 deaths), {followed} by heart problems (9). The trigger was unknown for one more 9 deaths. Different causes have been substance misuse (3), most cancers (3), diabetes (2), seizure (1) and bowel obstruction (1), and one loss of life was recorded as clozapine associated. Some deaths had multiple trigger recorded. Not one of the individuals who died had a purple or amber end result throughout 12-weekly monitoring, and no deaths have been attributable to agranulocytosis.
In abstract, there have been no instances of agranulocytosis and no deaths from agranulocytosis amongst long-term sufferers who moved to 12-weekly monitoring. Most sufferers (83%) stayed on 12-weekly monitoring for the remainder of the examine.
On this examine, the authors discovered an elevated variety of deaths from respiratory illness and used earlier research to notice that pneumonia may happen in those that begin clozapine remedy and suggested to place measures in place to scale back the chance of pneumonia such because the pneumococcal vaccine.
Conclusions
The authors concluded that it was protected to scale back the frequency of clozapine monitoring to 12-weekly in long-term clozapine sufferers. Nevertheless, it is very important contemplate the strengths and limitations of the examine earlier than drawing agency conclusions about wholesale adjustments to monitoring.
Strengths and limitations
This examine has a number of strengths. The analysis query was clear, and the outcomes (agranulocytosis, deaths from agranulocytosis and irregular blood outcomes) have been the suitable ones for judging security. Everybody within the pattern had the identical analysis and remedy. The pattern was massive: 1,025 sufferers {followed} up for a median of 4 years, or 3,366 person-years in complete. Blood outcomes got here from laboratory exams recorded by a UK clozapine monitoring service, the Zaponex Therapy Entry System, which reduces the chance of measurement bias. The pattern was additionally ethnically various (48% White, 30% Black, 11% Asian, 3% combined and eight% different) and included folks with benign ethnic neutropenia. The paper doesn’t say who was within the “different” group.
There are additionally essential limitations.
- First, there was no management group of sufferers on normal 4-weekly monitoring. This implies the examine can present that the chance was low on 12-weekly monitoring, however not that 12-weekly monitoring is as protected as 4-weekly.
- Second, the pattern was extremely chosen. Sufferers needed to have taken clozapine reliably for no less than a yr with no historical past of neutropenia, and on common that they had been taking it for 10 years. The danger of agranulocytosis is highest early in remedy and really low after that. So this was a low-risk group, and the findings could not apply to everybody at the moment on 4-weekly monitoring.
- Third, agranulocytosis is uncommon, so even a big examine can miss it. The authors cite an anticipated price after the primary yr of 0.31 to 0.52 instances per 1,000 person-years (Schulte, 2006). With no instances in 3,366 person-years, the true price may nonetheless be as excessive as about 0.9 per 1,000 person-years (the higher 95% confidence restrict). So the examine can not rule out a price at or above the same old background danger.
- Fourth, key particulars weren’t reported. The examine didn’t report clozapine dose, smoking standing (which impacts clozapine ranges), different medicines or previous medical historical past. Different medicines matter as a result of some, comparable to carbimazole, co-trimoxazole, carbamazepine and azathioprine, can even trigger agranulocytosis. We additionally don’t know what occurred to the 9 sufferers with a purple end result, why 9 deaths had an unknown trigger, or something concerning the one loss of life recorded as clozapine associated.
- Lastly, the information got here from solely one of many three UK clozapine monitoring providers. The outcomes could not mirror sufferers registered with the opposite two.
Implications for apply
After the primary yr of remedy, UK product licences at the moment require blood exams no less than each 4 weeks, so long as neutrophil counts are secure (Viatris, 2026; Leyden Delta BV, 2024). Agranulocytosis will not be the one motive to cease clozapine. Different probably severe blood situations, comparable to eosinophilia (a excessive stage of eosinophils, a kind of white blood cell) and thrombocytopenia (low platelets), additionally present up within the full blood depend. Any change to monitoring must preserve these in view.
Clozapine works for folks with treatment-resistant schizophrenia. It reduces hospital readmissions and lowers suicide danger (Fernandez-Egea et al., 2024), but it stays underused. Frequent blood exams are one motive: they’re a burden, they usually can lead folks to cease remedy or disengage from care.
This examine provides to the proof that 12-weekly monitoring could also be cheap for some individuals who have taken clozapine for a very long time and have secure blood counts. There have been no instances of agranulocytosis and no deaths from it. However this can be a single observational examine with no management group and a low-risk pattern, so by itself it’s not sufficient to alter apply for everybody.
The deaths on this examine additionally level to a special danger. Respiratory illness was the most typical reason behind loss of life, and no deaths have been as a consequence of agranulocytosis. Because the authors observe, pneumonia could matter extra for clozapine security than agranulocytosis. Measures such because the pneumococcal vaccine, and fast remedy of chest infections, deserve as a lot consideration because the blood take a look at schedule.
Blood exams are sometimes an everyday level of contact with providers. For individuals who dwell alone or have little assist, fewer exams may imply fewer probabilities to identify issues early or to ask for assist. However, frequent exams can really feel like a burden and should push some folks away from care. If blood exams develop into much less frequent, different contact with the care group ought to keep it up, in order that fewer exams don’t imply much less assist.
With fewer blood exams, folks will rely extra on recognizing and reporting the indicators of agranulocytosis themselves. These embrace fever, chills, flu-like signs, a sore throat or mouth sores, excessive tiredness, and weak spot attributable to a drop in blood strain. Clear info and good conversations about clozapine and its unintended effects are important. This can be tougher for older adults and for folks with cognitive impairment or impaired decision-making capability, who could discover it troublesome to recognise or talk new signs. They could want further assist from household, carers or workers.
Extra analysis is required earlier than tips change. Research that examine 12-weekly with 4-weekly monitoring, and systematic critiques that deliver the rising proof collectively, would assist. Any change to apply would additionally want settlement from the clozapine monitoring providers and adjustments to the product licences.
Statements of curiosity
WingYee declares no conflicts of curiosity and AI was not used within the improvement of the weblog.
Edited by
Dr Simon Bradstreet.
Hyperlinks
Major paper
David Taylor, Siobhan Gee, Marinka Helthuis, Ebenezer Oloyede. (2025) The Security of 12-Weekly Monitoring of Neutrophil Rely in Lengthy-Time period Clozapine Sufferers. Acta Psychiatr Scand. 2025 Sep;152(3):187-192.
Different references
Nationwide Institute for Well being and Care Excellence (2015) Psychosis and schizophrenia in adults. QS80.
Oloyede et al. (2023). Medical affect of lowering the frequency of clozapine monitoring: managed mirror-image cohort examine. 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 related to clozapine what’s the proof, The British Journal of Psychiatry, 225(3), pp.357-359.
