Clozapine

Clozapine is an antipsychotic drug that may be used to treat patients with schizophrenia who are unresponsive to, or intolerant of, conventional neuroleptics. It causes few extrapyramidal adverse effects and may be effective in combatting the negative symptoms of schizophrenia.

Clozapine has a relatively low affinity for D2 receptors and a much higher affinity for D4 receptors. Furthermore, it has some affinity for 5HT2 receptors. It is not clear exactly which aspects are responsible for its superior antipsychotic effect in treatment-resistant schizophrenia (1).

The major side effect is neutropaenia which is not dose-related and occurs in 1-2% of patients. For this reason, clozapine is contra-indicated in patients with a past history of neutropaenia. Information for prescribers regarding cardiac disease and clozapine and information regarding this is linked in the menu below.

One-third of patients with chronic intractable schizophrenia will respond within 6 weeks; about two-thirds within a year.

Monitoring (2)

• is a requirement that people taking clozapine have full blood counts (FBC) (particularly white cell count, neutrophils, and platelets) monitored by the manufacturer
  • is because clozapine can rarely cause fatal agranulocytosis, neutropenia, and thrombocytopenia
• monitoring is usually performed weekly for 18 weeks, then every 2 weeks for the rest of the first year, then every 4 weeks thereafter
  • if doses are missed, or if results are outside the required limits, the frequency of monitoring may be increased

Plasma level monitoring (2)

• MHRA (https://www.gov.uk/drug-safety-update/clozapine-and-other-antipsychotics-monitoring-blood-concentrations-for-toxicity) recommends monitoring plasma levels of clozapine for toxicity in certain clinical situations such as when:
  • a patient stops smoking or switches to an e-cigarette/NRT
  • concomitant medicines may interact to increase blood clozapine levels
  • a patient has pneumonia or other serious infection
  • reduced clozapine metabolism is suspected
  • toxicity is suspected

• clozapine dose may need to be reduced in the case of stopping smoking or severe infection to reduce the risk of toxicity
• plasma levels need to be reviewed if patients start/restart smoking

Target range

• therapeutic window of 0.35 mg/L to 0.6 mg/L is recommended (2)

Inadequate response to antipsychotic treatment in schizophrenia and use of clozapine (1)

• clozapine should be used if symptoms have not responded adequately despite sequential use of at least two different antipsychotics, one of which should be a non-clozapine second-generation antipsychotic
  • if symptoms have not responded adequately to an optimised dose of clozapine, review the diagnosis, adherence to treatment, engagement with and use of psychological treatments, and other possible causes of non-response and measure therapeutic drug levels before offering a second antipsychotic to augment clozapine. The second drug should not compound the common side effects of clozapine. An adequate trial of augmentation may need to be up to 8-10 weeks

Recommendations for routine blood count monitoring for the risk of agranulocytosis (3)

Clozapine increases the risk for neutropaenia and agranulocytosis. Regular blood count monitoring is in place to minimise this risk. New evidence has led to revised monitoring recommendations.

Revised Absolute Neutrophil Count (ANC) thresholds

• the monitoring requirement for White Blood Cell (WBC) count has been removed since the Absolute Neutrophil Count (ANC) is sufficient
• ANC thresholds for treatment initiation and continuation have been amended in line with the standard definitions of mild (ANC: 1000–1500/mm³), moderate (ANC: 500–999/mm³), and severe neutropenia (ANC <500/mm³)
• initiation of clozapine is only recommended in patients with ANC ≥1500/mm3 (≥1.5x109/L) and in patients with confirmed BEN (benign ethnic neutropaenia) with ANC ≥1000/mm3 (≥1.0x109/L)

Revised ANC monitoring requirements:

The patient’s ANC must be monitored as follows:

• weekly during the first 18 weeks of treatment
• then monthly for the following 34 weeks (i.e., until completion of the first year of treatment)
• if there has been no history of neutropaenia during the first year of treatment, ANC monitoring can be reduced to once every 12 weeks
• if there has been no history of neutropaenia during the first two years of treatment, ANC should be collected once a year
• patients should be reminded at each consultation to contact their physician immediately if signs or symptoms of infection occur
  • in the event of such symptoms, ANC must be performed immediately
• additional ANC monitoring may be considered in older patients, or with concomitant treatment with valproic acid, especially during the initiation period

Actions to be taken depending on ANC values:

• the ANC of patients who experience mild neutropaenia (1000-1500/mm3) during treatment that subsequently stabilises and/or resolves, should be monitored monthly throughout treatment. For patients with confirmed BEN the threshold is ANC: 500-1000/mm3 (0.5-1.0 x109/L)
• patients with an ANC <1000/mm3 (<1.0x109/L) must immediately stop treatment and not be re-exposed
  • for patients with confirmed BEN the threshold is ANC <500/mm3 (<0.5x109/L)
• patients should be monitored weekly for 4 weeks in case of complete discontinuation

Recommendations for ANC monitoring upon resuming clozapine after treatment interruption for non-haematological reasons:

• stable patients (≥2 years of treatment) without neutropaenia can resume their previous schedule, irrespective of the duration of the interruption
• patients with prior neutropaenia or shorter treatment duration (>18 weeks-2 years) need closer monitoring after interruptions ≥3 days but less than 4 weeks
• patients who interrupted treatment for ≥4 weeks require weekly monitoring and re-titration, regardless of previous duration of treatment and prior mild neutropaenia

The summary of product characteristics should be consulted before prescribing this drug.

Reference:

1. NICE (2010). Schizophrenia Core interventions in the treatment and management of schizophrenia in adults in primary and secondary care
2. NHS Specialist Pharmacy Service (June 28th 2024). Clinical considerations for patients prescribed clozapine
3. European Medicines Agency (September 9th 2025). Clozapine - direct healthcare professional communication (DHPC)