Initiation

Clozapine titration requires slow dose escalation, typically starting at 12.5 mg/day in both adults and children, however in the community dosage can start as low as 6.25 mg (R.K., personal communication, 2025). Close monitoring of white blood cell count, neutrophils and physical observations is required. Clozapine services can be delivered via formal clozapine clinics (which provide structured monitoring and support, enhancing adherence and safety) or ad hoc arrangements (effective in resource-limited settings, but requiring clear protocols and consistent communication) (European Medicines Agency 2023).

Initiation in hospital ensures close supervision during the critical titration phase, and may be especially appropriate in more complex cases, for example for those deemed to be at higher risk owing to psychotic symptoms or medical comorbidity. Community initiation, although less common, is feasible with robust infrastructure and multidisciplinary support, but restrictions in what is available locally, especially in the context of child and adolescent psychiatry services, may limit this (Walker Reference Walker, Lang and Smith2024). There are promising developments in the area of community initiation, for example in the use of virtual wards by Cambridge University Hospitals NHS Foundation Trust (R.K., personal communication, 2025). Such an environment allows patients to get the care they need safely and conveniently at home, rather than being in hospital.

UK clozapine brands and monitoring services

The following brands of clozapine are available in the UK, and each has its own monitoring service:

• • Clozaril® tablets: the Clozaril Patient Monitoring Service (CPMS)

• • Denzapine® tablets and oral suspension: the Denzapine Monitoring System (DMS)

• • Zaponex® tablets and orodispersible tablets: the Zaponex Treatment Access System (ZTAS).

These monitoring services centrally track leucocyte and neutrophil counts (via a white cell count or full blood count) at the specified intervals outlined in Box 1. In the UK, this monitoring is mandatory for all patients prescribed clozapine (European Medicines Agency 2023) and clozapine use is restricted to individuals registered with an appropriate monitoring service. Additionally, prescribing physicians must register both themselves and a designated pharmacist with the service. All patients receiving clozapine must be under the supervision of a qualified specialist, and its supply is limited to hospital and community pharmacies that have local agreements for dispensing – it is not sold to or distributed through wholesalers (European Medicines Agency 2023).

Monitoring requirements in the USA, Europe and UK

In early 2025, the US Food & Drug Administration (FDA) announced a significant change regarding the monitoring requirements for clozapine in the country (US Food & Drug Administration 2025). The FDA has decided to discontinue the Risk Evaluation and Mitigation Strategy (REMS) programme, which previously mandated that prescribers, pharmacies and patients participate in routine reporting of absolute neutrophil count (ANC) tests prior to dispensing the drug. Although ANC monitoring remains essential and should continue according to the prescribing guidelines, the removal of the REMS programme is expected to alleviate the administrative burden on healthcare providers and improve patient access to clozapine in the USA. The FDA has communicated these changes to manufacturers and is working with them to update the prescribing information accordingly, ensuring that the risk of neutropenia continues to be clearly communicated through boxed warnings and other labelling (US Food & Drug Administration 2025).

Parallel developments have occurred in Europe, where the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency has issued updated guidance on blood monitoring for clozapine (European Medicines Agency 2025). These recommendations include reducing the frequency of ANC monitoring in patients without neutropenia, extending intervals to every 12 weeks after 1 year of treatment and annually after 2 years. Importantly, the guidance emphasises the use of ANC as the sole laboratory marker for monitoring, discontinuing the requirement to measure total white blood cell counts. This adjustment reflects current evidence underscoring ANC as the most relevant indicator of neutropenia risk. Product information across all clozapine-containing medications will be revised to reflect these changes, including updated thresholds for treatment initiation and continuation (European Medicines Agency 2025). The UK is anticipated to follow suit, revising its guidance to align with these international updates, which collectively aim to streamline monitoring processes while maintaining patient safety.

In the UK, if samples are analysed locally, results must be shared with the appropriate clozapine monitoring service, assigning a coloured ‘status’ (green, amber, red) that might indicate the need for more frequent monitoring (Table 1).

TABLE 1

Colour classification of mandatory blood testing during clozapine monitoring in the UK

WBC, white blood cell; neutrophils, absolute neutrophil count.

Source: reproduced with slight modification from Healthcare Improvement Scotland (2023).

Monitoring of blood clozapine levels is advised in certain clinical situations as detailed in Box 2. Prescribing clinicians should ultimately be guided by the blood plasma level and not the total oral dose of clozapine (Stahl Reference Stahl and Strawn2024).

As the clozapine dosage is slowly titrated up, there should be regular monitoring for effectiveness. Monitoring must also include active discussion and screening for side-effects and adverse effects (see below), alongside physical health evaluations, periodic plasma clozapine monitoring (when appropriate) and enhanced training for psychiatrists, mental health staff, patients and carers, as well as healthcare professionals in primary and tertiary settings involved in patient care (Fernandez-Egea Reference Fernandez-Egea, Flanagan and Taylor2024). If clinical efficacy of clozapine continues to be questioned despite dosing being optimised, Box 3 outlines further considerations for the care plan.

The quantity of clozapine dispensed in each prescription aligns closely to the phase of the blood monitoring schedule in place. This ensures patients do not have a surplus of the drug in the event of blood discrepancies that require discontinuation or a dosage reduction. As regards prescribing, plasma half-life suggests twice-daily administration, but in practice it may be given once a day at night, especially for older adolescents (Stahl Reference Stahl and Strawn2024).

Switching, augmentation and high-dose prescribing

Prescribers and pharmacists must follow brand-specific prescribing and dispensing guidelines for clozapine to avoid disrupting effective monitoring that could occur if patients switch brands. To ensure patient safety, patients should be prescribed only one brand of clozapine at a time and, as noted above, be registered with the monitoring service associated with that brand (European Medicines Agency 2023).

Augmentation of clozapine with another psychotropic should be considered only after optimised clozapine treatment has been administered for at least 3 months (Barnes Reference Barnes, Drake and Paton2020). If satisfied that there is no other cause for non-response, CG155 recommends augmenting clozapine treatment with a second antipsychotic. An adequate trial of augmentation may need to continue for 8–10 weeks (NICE 2013). The antipsychotic used for augmentation should possess a receptor profile that complements clozapine and a side-effect profile that avoids exacerbating clozapine-related issues, including sedation, weight gain and metabolic disturbances (Barnes Reference Barnes, Drake and Paton2020).

Prescribing high-dose antipsychotics should be considered only if adequate trials of antipsychotic monotherapy and augmentation, including a trial of clozapine, have failed. Local guidelines for identification and monitoring of patients receiving high-dose antipsychotics should be developed and followed (SIGN 2013).

Interruption and discontinuation

If clozapine treatment is paused for over 48 hours, it should be restarted at a maximum of 12.5 mg once or twice daily. Provided this is well tolerated, without cardiovascular or respiratory complications, and the prior titration was uneventful, the dose can then be increased to the therapeutic level more quickly than the standard initiation schedule (Barnes Reference Barnes, Drake and Paton2020).

If clozapine is to be discontinued, where possible the dose should be gradually tapered over at least 1–2 weeks. Following discontinuation – especially if abrupt, as in cases of agranulocytosis – the patient’s physical and mental condition should be closely monitored for signs of cholinergic rebound or a rapid return of psychotic symptoms, particularly during the first week (Barnes Reference Barnes, Drake and Paton2020). Abrupt discontinuation of clozapine is associated with withdrawal symptoms that are both more common and more severe than those seen with other antipsychotics (Stahl Reference Stahl and Strawn2024).

Diagnosis and risk factors for schizophrenia

There can be a reluctance to make certain diagnoses in child and adolescent psychiatry services in general. This has historically been a challenge in relation to psychosis and, more recently, personality disorder (Schmeck Reference Schmeck2022). Perhaps clinicians can be reluctant to diagnose young people with schizophrenia as it is seen as a long-term diagnosis that could be difficult to explain to a family. This can prevent patients from receiving correct treatment. Childhood psychosis-like symptoms may be linked to multiple other mental disorders or neurodevelopmental conditions, such as major mood disorders, autism and dissociative states. Prodromal illnesses and presentation of affective disorders can also be highly variable in young people, which can lead to a delay in diagnosis of psychosis or schizophrenia (Pattnaik Reference Pattnaik, Panda and Chandran2023).

Both childhood- and adult-onset schizophrenia share several similar factors, including genetic risk factors and grey matter alterations on neuroimaging (Di Luzio Reference Di Luzio, Pontillo and Villa2023). Nevertheless, childhood-onset schizophrenia exhibits several distinct and identifiable features, including a generally more severe clinical presentation (especially in females), a higher prevalence of visual hallucinations and elevated rates of co-occurring neurodevelopmental differences (Di Luzio Reference Di Luzio, Pontillo and Villa2023).

Clozapine-related adverse effects and tailored dosing

Children and adolescents taking clozapine may face a greater risk of cardiac and metabolic side-effects compared with other atypical antipsychotics (such as aripiprazole, olanzapine, quetiapine and risperidone) (Pattnaik Reference Pattnaik, Panda and Chandran2023). Clozapine has also been linked to increased rates of behavioural difficulties and white blood cell abnormalities in children. Nevertheless, despite these reported side-effects and the higher susceptibility to metabolic syndrome, children are generally less likely than adults or older adults to experience side-effects from clozapine (Pattnaik Reference Pattnaik, Panda and Chandran2023).

Young people who are prescribed clozapine may be at a higher risk than adults for developing seizures and epileptic discharges (identified on electroencephalogram (EEG). Therefore, clinicians might consider conducting a pretreatment EEG and might also opt for follow-up EEG testing after starting treatment if there is significant change in the individual’s behaviour (Roub Reference Roub, Dar and Dar2023). However, EEG changes do not indicate the risk of seizure, in absence of any relevant clinical symptoms. The most common seizure type during clozapine use is generalised tonic-clonic seizures, and therefore EEG has a limited role in monitoring and predicting seizures (Roub Reference Roub, Dar and Dar2023). Since the risk of clozapine-related seizures appears to be dose-dependent, one approach to minimising this risk is to use the lowest effective dose of clozapine for the particular individual (Yadav Reference Yadav2022). Given the possibility of lifelong treatment, increased caution is recommended when using clozapine for children with a history of diabetes or hyperlipidaemia, or for those with a history of these conditions in first-degree relatives (American Academy of Child and Adolescent Psychiatry 2011).

Young people may have increased sensitivity to adverse effects, requiring tailored monitoring and support. They may respond with lower clozapine plasma levels than those expected for efficacy in adults. To ensure safe prescribing, dose titration should be incremental. Current titration of clozapine in young people follows the widely accepted standard adult initiation schedule (Taylor Reference Taylor, Barnes and Young2021b); however, dose increases are of smaller increments and with longer titration duration in most cases. Prescribing in this way promotes early identification of adverse effects, with tolerability and efficacy being assessed throughout. There is no current widely agreed standard initiation schedule for young people, and generally an adult clozapine titration schedule is adapted and used in clinical practice.

The transition to adult psychiatric services

Transitioning to adult mental health services can be a time of worry, distress and change for a young person, given the need to form new relationships with care teams (Paul Reference Paul, Street and Wheeler2015). Prescribing clozapine should not negatively affect the young person at the point of transition and instead could be viewed as a stabilising factor, given the support this would give in reducing relapse at a time of potential destabilisation.

On transition, the name of the prescribing physician registered with the Clozapine Patient Monitoring Service will require updating (European Medicines Agency 2023), but there is no requirement for treatment to be interrupted. Monitoring requirements will continue as indicated at that time point. Careful communication and handover should take place between child and adolescent and adult services, to ensure that there is no break in monitoring of both psychotic symptoms and possible physical side-effects. Continuity of treatment can be aided by use of safeguarding processes for vulnerable adults, in liaison with social workers, involving multi-agency assessment and high-quality transitional care provision (Paul Reference Paul, Street and Wheeler2015).

Emerging and future research

Having an awareness of current research in mental health areas is fundamental in ensuring ongoing evidenced-based prescribing. A limiting factor for clozapine use in young people is the ability to obtain the required blood results, as many children are fearful of venepuncture and associated pain (Kleye Reference Kleye, Heden and Karlsson2021). Emerging research indicates a role for capillary testing in favour of traditional sampling methods (Taylor Reference Taylor, Atkins and Harland2021a). This less invasive route might reduce young people’s anticipatory stress, making them more willing to cooperate with monitoring requirements, thus removing a current barrier to clozapine prescribing and resulting in increased clozapine use in this age group.

Another promising avenue for clozapine is the importance of pharmacogenomics to treatment outcomes. Clozapine is metabolised by the cytochrome P450 (CYP450) enzymes, with the CYP1A2 enzyme being predominantly involved. CYP1A2 activity might therefore be linked to optimal clozapine dosing (Ruan Reference Ruan and de Leon2020). Further understanding of this could determine the inter-individual variability within the current therapeutic drug monitoring range, reducing risks of adverse effects and improving prediction of clinical response at the point of prescribing.

Research is showing that ancestral effects also link with clozapine metabolism. Individuals of African ancestry are more likely to be fast clozapine metabolisers, whereas those of Asian ancestry are more likely to be slow clozapine metabolisers (Pardinas Reference Pardinas, Kappel and Roberts2023). Applying such knowledge at the patient level could result in reduced risk of toxicity and improved tolerance of clozapine, therefore reducing delay in clozapine initiation due to concerns.

The literature on clozapine use for younger people is limited to a few case series only, and large controlled studies are needed to elucidate population-based side-effects of clozapine (Pattnaik Reference Pattnaik, Panda and Chandran2023). The need for well-designed large-scale, long-term randomised controlled trials to further evaluate the role of clozapine in the management of child- and adolescent-onset schizophrenia has been emphasised (Adnan Reference Adnan, Motiwala and Trivedi2022). Addition of childhood-onset psychosis to, for example, England’s national rare disease lists (Department of Health & Social Care 2025) might help ensure that further funding is made available to those in need of it. It might also be helpful to consider funding clozapine monitoring clinics serving patients of all ages, given the challenges that psychiatrists have in reliably accessing clozapine clinics for child and adolescents (Walker Reference Walker, Lang and Smith2024).