In their narrative review, Walker et al (Reference Walker, Little and Haridas2026: this issue) summarise important themes regarding safe prescribing of clozapine in young people and highlight a clear unmet need for training and education. In an editorial in The Lancet in January 2024, John Kane, who is undoubtedly one of the foremost experts on clozapine, was quoted saying ‘I’ve spent my life doing clinical research, but then at some point you realise that the real obstacle is getting people to implement the findings… It’s a shame when patients are not provided the opportunity to benefit from something that might be very helpful for them’ (The Lancet Psychiatry 2024).
The evidence base
The evidence for clozapine in treatment-resistant schizophrenia in adult populations is overwhelming, with a plethora of robust systematic meta-reviews demonstrating benefits over non-clozapine antipsychotics. These range from patient-specific outcomes such as improvements in positive symptomatology, reduction in suicidality and lower overall mortality to system-level outcomes, including reduced hospital bed usage and financial savings. Evidence consistently indicates that clozapine exerts a protective anti-suicidal effect, which is particularly significant since people with schizophrenia experience substantially elevated suicide risk relative to the general population (De las Cuevas Reference De las Cuevas, de Leon and Blasco-Fontecilla2025).
Despite the wealth of evidence for clozapine in adult schizophrenia, studies exploring child and adolescent populations are few and notably smaller owing to the lower incidence of schizophrenia in these populations. However, at present, there is no reason to suspect the effectiveness in young people with treatment-resistant schizophrenia, although more research is clearly needed. Walker et al (Reference Walker, Little and Haridas2026) summarise available literature and draw attention to important considerations for prescribing in young people, including potential differences in incidence of adverse effects compared with adult populations.
Reasons for avoiding clozapine
Cardio- and cerebrovascular effects
One of the common prescriber-cited reasons for avoiding clozapine is the potential for metabolic adverse effects, an issue that may be more pertinent when prescribing clozapine in young people. However, this concern is contradicted by the large systematic review by Correll et al (Reference Correll2022), which demonstrates that despite the high adverse effects burden, clozapine reduces the risk of natural mortality, including that due to cardiovascular and cerebrovascular causes, by 50%, so although clinicians must remain mindful of clozapine’s potential adverse effects, these should not pose a barrier to appropriate use. Given the poor prognostic indicator inherently linked to early-onset schizophrenia and the potential for reduced clozapine efficacy by delaying initiation, a proactive and algorithmic approach to pharmacological treatment is imperative to offer patients the best chance of positive outcomes.
Neutropenia
A systematic review of clozapine management of child- and adolescent-onset schizophrenia found a neutropenia incidence of 6–15%, which is higher than in adults, although reassuringly, the agranulocytosis rate was <0.1% (Adnan Reference Adnan, Motiwala and Trivedi2022). This higher incidence may be concerning, but it is worth highlighting that the threshold for neutropenia was classified as an absolute neutrophil count below 1500/mm3, which corresponds to mild neutropenia that does not carry life-threatening consequences. Under the US Food and Drug Administration (FDA) criteria, only a few of these cases would likely necessitate a break in clozapine therapy and, importantly, if the Medicines & Healthcare products Regulatory Agency (MHRA) in the UK mirrors the FDA recommendations allowing continuation of clozapine with neutrophil counts >1000/mm3, the adverse effects of unnecessary clozapine discontinuation could be avoided. As Walker et al (Reference Walker, Little and Haridas2026) mentioned, recent changes in European Medicine Agency (EMA) guidance on clozapine prescribing include blood monitoring for neutropenia. In these guidelines, monitoring has shifted to absolute neutrophil count (ANC) only and becomes far less frequent after the early treatment period. After 1 year it can drop to 12-weekly, and after 2 years to annual testing for patients without prior neutropenia.
This is because the current evidence suggests that the risk of agranulocytosis is primarily restricted to the first 2 years of initiation (more so to the first 18 weeks) – after that, the risk is not very different from other antipsychotic drugs (Northwood Reference Northwood, Myles and Clark2024). Agranulocytosis can be managed effectively with medications such as granulocyte colony-stimulating factor, and the fatality rate is about 5% (Gupta Reference Gupta, Bannon and Nodiyal2025). In comparison to agranulocytosis, the risk of fatality is much higher from pneumonia and associated clozapine toxicity and constipation-related adverse effects (such as intestinal obstruction or paralytic ileus). Monitoring and management of these higher-risk adverse effects should be prioritised, instead of specifically focusing only on neutropenia.
Preventing or managing side-effects
The vast majority of clozapine side-effects are preventable and/or manageable with appropriate screening and prompt intervention. As most of the adverse effects appear early (such as agranulocytosis or myocarditis) and might also be dose-related (such as sedation, hypersalivation, constipation), slow and individualised titration is required (de Leon Reference de Leon, Schoretsanitis and Smith2022). Therapeutic drug monitoring and close monitoring of adverse effects to inform the titration should be considered. Point-of-care plasma level monitoring is a new development and is increasingly being adopted by the National Health Service (Taylor Reference Taylor, Atkins and Harland2021).
The practice of a standard dose titration for all patients might not be appropriate, as a significant proportion of individuals discontinue clozapine owing to manageable adverse effects, especially within the first 12 months of initiation (Legge Reference Legge, Hamshere and Hayes2016). There is also emerging evidence of the utility of C-reactive protein (CRP) to guide the rate of titration, as clozapine-induced fever and inflammation can decrease its metabolism (de Leon Reference de Leon, Schoretsanitis and Smith2022). Furthermore, individuals with Asian ancestry often require reduced dosages relative to people from other ancestral groups.
Conclusion
Overall, the available evidence and guidelines continue to promote early, proactive use of clozapine for treatment-resistant schizophrenia in patients of all ages, amid persistent perceived or actual barriers to treatment. The educational review by Walker et al (Reference Walker, Little and Haridas2026) provides another resource in the Sisyphean task of tackling the global under-utilisation of clozapine.
Author contributions
S.G. and M.C. jointly contributed to the conception and writing of the manuscript. Both authors conducted the literature search. M.C. prepared the initial draft, and S.G. critically reviewed, revised and finalised the manuscript.
Funding
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Declaration of interest
Both S.G. and M.C. have received lecture fees from Viatris, one of the manufacturers of clozapine.
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