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. There has also been a recent update to 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

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