After two years of clean blood counts, experts recommend a major shift in monitoring
STUDY: Siskind D et al, Lancet Psychiatry 2026;13(1):77–86
STUDY TYPE: Expert consensus (Delphi panel)
FUNDING: Independent
Background
In 2025, the US FDA ended the REMS program for monitoring neutrophils on clozapine, but they failed to step in with new guidance. Now guidance from US and international experts steps in.
The Study
- 76 clozapine experts (64 psychiatrists, 12 pharmacists) from every continent completed the first survey round, and 84 completed the second.
- Most had more than 10 years in schizophrenia care, and two-thirds had treated over 100 clozapine patients.
- Consensus required 75% agreement across two rounds in late 2024.
- Five patients taking clozapine reviewed the final algorithm and checklist in a focus group.
Results
For neutrophil monitoring, the panel agreed on these steps:
- Check the absolute neutrophil count (ANC) weekly for 18 weeks (96% agreement), then every 4 weeks.
- Stop routine ANC monitoring at 2 years (85%). Only 5% favored lifelong testing.
- Consider stopping clozapine below 1.0 × 10⁹/L (78%), or below 0.5 × 10⁹/L for patients with Duffy-null benign ethnic neutropenia (83%).
- After 2 years, look for other causes (valproate, infection, chemotherapy) before stopping.
- Order an annual complete blood count to screen for blood cancers. These are slightly more common on clozapine (61 vs 41 cases per 100,000 person-years).
The two year cut-off for routine neutrophil monitoring is based on large cohort studies. For example, in a database of over 26,000 Australian and New Zealand patients, weekly incidence peaked at 9 weeks and fell to 0.001% by 2 years.
Check for side effects, with a standard checklist at each blood draw for the first two years, then every three months. The Mayo Clinic uses the Glasgow Scale. The expert panel recommends checking weight and metabolic syndrome, constipation, reflux, drooling, sedation, bedwetting, orthostatic hypotension, tachycardia, sleep apnea, seizures, OCD symptoms, and pneumonia.
Where available, check clozapine levels annually and whenever smoking changes, infection develops, side effects shift, or a CYP1A2 inhibitor starts or stops. The panel did not recommend annual echocardiograms, and annual ECGs fell short of consensus (63%).
A US Alternative
Recently, four U.S. clozapine experts endorsed the expert guidance above and offered a slight variation in a JAMA Psychiatry editorial:
- Weekly ANC for 18 weeks, then monthly to 1 year.
- Long-term patients without past neutropenia: quarterly or yearly counts after 1 to 2 years.
The US guidance is similar for the first year. It is lighter in some ways, but stronger in recommending ongoing, infrequent checks after two years.
Practice Implications
- Mortality on clozapine is not just due to neutropenia. Ileus from severe constipation is the leading cause; learn more about the medical and dietary steps to prevent this problem on clozapine.
- The two year cut-off is based on large cohort studies, but before you drop ANC monitoring, check local regulations, which vary by country and state.
- Start a prophylactic laxative (senna, docusate, or both) in every clozapine patient.
- There’s more expert tips on managing clozapine in Jonathan Meyer’s book.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
