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4.5 Clozapine

Clozapine, a dibenzodiazepine derivative, is an effective antipsychotic but unlike many older antipsychotics, it is a relatively weak antagonist1 at the dopamine D2 receptor. Clozapine acts relatively strongly at the dopamine D4 receptor and it has antimuscarinic2, antihistaminic3 and antiserotonergic, and alpha-adrenergic blocking properties.

Clozapine is associated with a risk of agranulocytosis4 and, for this reason, it should be considered for the treatment of schizophrenia5 only if other antipsychotics cannot be used (either because they have proved ineffective or because they produce severe and untreatable adverse effects); clozapine is also indicated for psychotic disorders in Parkinson’s disease where standard treatment has failed.


The risk of convulsions is greater with clozapine than with other antipsychotics — see under convulsion.

Clozapine is also very commonly associated with hypersalivation (excessive drooling, sialorrhoea), which can be very embarrassing for the patient and compromise adherence to treatment but it can also be life-threatening if saliva is aspirated. Hypersalivation is often dose-related and improves with time, but it can occasionally be persistent.

In addition to the adverse effects associated with other antipsychotics, serious (though relatively rare) risks of clozapine are:

  • Agranulocytosis. Clozapine has caused fatalities, but the incidence has decreased with the institution of a strict prescribing protocol and rigorous regimen for blood tests
  • Myocarditis. Myocarditis, which has been associated with fatalities, most often occurs in the first two months of clozapine treatment
  • Cardiomyopathy. Cardiomyopathy generally develops some time after starting clozapine treatment.
  • Impaired intestinal peristalsis. Clozapine can cause constipation, intestinal obstruction, faecal impaction and paralytic ileus; these effects have been associated with fatalities.

It is essential to follow the official recommendations on the use of clozapine and on registering patients in the patient monitoring service — see summary of product characteristics7 and other product literature

Factors that increase risk

History of cardiac disorders or of primary bone marrow disorders might increase the risk of serious adverse effects; therefore, when considering clozapine for such patients, advice should be taken from the respective specialist.

Resuming clozapine treatment after an interruption of more than three days may increase the risk of blood disorders, calling for monitoring of white blood cell count and of absolute neutrophil count every week for 6 weeks (for 18 weeks if treatment interrupted for longer than 4 weeks).

Clozapine should not be given concurrently with a prolonged-release antipsychotic injection, nor should it be started until the prolonged-release antipsychotic has been washed out completely. This is because presence of prolonged-release antipsychotic could seriously impair recovery from clozapine-induced leucopenia.

The risk of gastrointestinal effects is increased by concomitant use of drugs that cause constipation (eg opioids and antimuscarinic drugs such as antiparkinsonian drugs and antidepressants) or in patients with a history of colon disorders or gastrointestinal surgery.

Risk-reduction measures

To avoid exposing patients to undue risk, clozapine must be prescribed according to official recommendations, in full compliance with the monitoring regimen specified—see summary of product characteristics.

Clozapine treatment should be initiated at a particularly low dose and the dose increased gradually.

A full medical history should be taken and the patient examined for features of cardiac disorders. Myocarditis and cardiomyopathy may be difficult to diagnose and it is important to watch for and investigate features such as persistent tachycardia, heart failure (fatigue, shortness of breath, oedema), arrhythmias, and symptoms mimicking myocardial infarction. In case of any suspicion of cardiac disorders, the patient must be evaluated urgently by a cardiologist. Clozapine must never be prescribed to patients who have developed clozapine-induced myocarditis or cardiomyopathy.

The patient and carers should be advised (and reminded at each consultation) of the need to seek medical help promptly for any features of blood disorders (eg sore throat, fever, unexplained bruising, infection or non-specific illness); they should be advised that a blood test will be necessary. Similarly, the patient and carers should promptly report any features suggestive of myocarditis or cardiomyopathy.

Because of the risk of gastrointestinal obstruction, drugs that cause constipation (eg opioids and antimuscarinics8) should either be avoided or steps taken to reduce the risk (eg reviewing doses of constipating medicines, taking adequate fluid, and considering use of a laxative). The use of clozapine in patients with a history of bowel disorder should be carefully evaluated.

The patient should be advised of the importance of adherence and that unless there are features of severe toxicity, clozapine should not be stopped abruptly. If treatment is interrupted, clozapine may need to be reinitiated with a small dose and the dose increased to the previous maintenance dose.


Development of significant blood disorder (see summary of product characteristics for details) calls for cessation of clozapine treatment and management may need to be guided by a haematologist. Similarly, if a cardiac disorder occurs, the patient should be referred immediately to a cardiologist and clozapine treatment stopped.

Constipation can be treated with laxatives, but more serious features such as intestinal obstruction require specialist referral.

For hypersalivation, consideration should be given to reducing the dose of clozapine; non-pharmacological methods, such as sugar-free chewing gum may help to increase swallowing of excessive saliva. Drug treatment (eg with antimuscarinics or with adrenoceptor agonists9 or antagonists) may be necessary for troublesome hypersalivation, but there is little compelling evidence to guide choice of treatment—specialist advice should be sought.

This learning module discusses noteworthy risks for antipsychotics. Summaries of product characteristics and the BNF should be consulted for a fuller account of the adverse effects and warnings for individual antipsychotics.

  1. A substance that binds to a receptor but produces no effect and inhibits an agonist from binding to the receptor
  2. Reduction or blocking of the effects of parasympathetic nerves; antimuscarinic effects include dry mouth, difficulty swallowing, blurred vision, confusion, palpitations, constipation, and urine retention
  3. A substance that blocks the effects of histamine. Histamine is released when the body mounts an immune response; also, histamine is a neurotransmitter and it regulates the functioning of the gastrointestinal system. Of the histamine receptors; histamine H1 receptor is involved in immune reactions, motion sickness and sleep regulation, while histamine H3 receptor is activated by histamine acting as a neurotransmitter
  4. Marked deficiency of a type of white blood cells (granulocytes) essential for immune functioning
  5. A mental disorder which affects how the individual feels, behaves and thinks
  6. A mental disorder which affects how the individual feels, behaves and thinks
  7. Summary of product characteristics, a document that forms the basis of information for European Union health professionals on how to use a medicinal product safely and effectively; it reflects the data assessed for granting marketing authorisation
  8. Reduction or blocking of the effects of parasympathetic nerves; antimuscarinic effects include dry mouth, difficulty swallowing, blurred vision, confusion, palpitations, constipation, and urine retention
  9. A chemical substance that binds to a receptor and mimics the effect of the physiological (endogenous) substance binding to the receptor