GENERIC NAME: clozapine

BRAND NAME: Clozaril

DRUG CLASS AND MECHANISM: Clozapine is an anti-psychotic medication that works by blocking receptors in the brain for several neurotransmitters (chemicals that nerves use to communicate with each other) including dopamine type 4 receptors, serotonin type 2 receptors, norepinephrine receptors, acetylcholine receptors, and histamine receptors. Unlike traditional anti-psychotic agents, such as chlorpromazine (Thorazine) and haloperidol (Haldol) as well as the newer anti-psychotics, risperidone (Risperdal) and olanzapine (Zyprexa), clozapine only weakly blocks dopamine type 2 receptors.

PRESCRIPTION: Yes

GENERIC AVAILABLE: Yes

PREPARATIONS: Tablets: 25 and 100 mg.

STORAGE: Tablets should be kept below 30°C (86 °F).

PRESCRIBED FOR: Clozapine is use in the management of psychotic disorders including schizophrenia.  Because of  concern for the side effect of agranulocytosis (see side effects), clozapine should be reserved for patients who have failed to respond to other standard medications or who are at risk for recurring suicidal behavior.

DOSING: Clozapine is given once, twice, or three times daily. The dose often is increased slowly until the optimal dose is found. The full effects of clozapine may not be seen until several weeks after treatment is begun.

DRUG INTERACTIONS: Risperidone (Risperdal) may cause an increase in the amount of clozapine in the blood. This could lead to an increased risk of side effects from clozapine.

PREGNANCY: There are no adequate studies of clozapine in pregnant women. Studies in animals suggest no important effects on the fetus. Clozapine can be used in pregnancy if the physician feels that it is necessary.

NURSING MOTHERS: Animal studies suggest that clozapine is secreted in breast milk. Therefore, women taking clozapine should not nurse their infants.

SIDE EFFECTS: Clozapine may cause a severe reduction in white blood cell count, a condition known as agranulocytosis, in approximately 1 in 100 patients who take it for at least one year. White blood cells fight infections, and a severe reduction in white blood cells can result in severe infections. If not caught early, agranulocytosis can be fatal. Therefore, the white blood cell count should be measured (with a blood test) prior to starting treatment and regularly (weekly) while patients receive this medication, and for 4 weeks after it is stopped.

Among elderly patients with dementia-related psychosis, treatment with clozapine is associated with an increased risk of death for unclear reasons.  Clozapine is not approved for use in dementia-related psychosis.

Seizures have occurred in approximately 1 of every 20 to 30 persons receiving clozapine. Patients receiving higher doses seem to be at higher risk.

Dizziness may occur in 1 of 5 persons taking clozapine. In some cases this may be due to orthostatic hypotension, a marked decrease in blood pressure that occurs when going from a lying or sitting position to a standing position.  The drop in blood pressure may lead to loss of consciousness or even cardiac and respiratory arrest.  This reaction is more common during the first few weeks of therapy while the dose is increasing, when drug is stopped briefly, or when patients are taking benzodiazepines such as diazepam (Valium) or other anti-psychotic drugs.

The most common side effect of clozapine is drowsiness.  Other side effects include increased heart rate, increased salivation, headache, tremor, low blood pressure, and fever. Clozapine has anticholinergic effects that interfere with the function of smooth muscles.  This can lead to blurred vision and difficulty urinating (when there is enlargement of the prostate) due to effects on the muscles of the eye and bladder.  Clozapine slows the intestine and leads to constipation in approximately 14% of patients.  Paralysis of the intestinal muscles can lead to paralytic ileus, a condition in which the intestine stops working.

Clozapine also may cause extrapyramidal effects (sudden, often jerky, involuntary motions of the head, neck, arms, body, or eyes). Like other anti-psychotics, clozapine also may cause tardive dyskinesia (potentially irreversible involuntary movements). The risk of such reactions appears to be lower with clozapine than with older anti-psychotics, perhaps due to its weaker effects on dopamine type 2 receptors.

Although there is no clear link between clozapine and diabetes, patients should be tested during treatment for elevated blood-sugars. Additionally, persons with risk factors for diabetes, including obesity or a family history of diabetes, should have their fasting levels of blood sugar tested before starting treatment and periodically throughout treatment to detect the onset of diabetes. Any patient developing symptoms that suggest diabetes during treatment should be tested for diabetes.

Clozapine is eliminated from the body by enzymes (P450) in the liver.  Numerous medications can increase or decrease the activities of these enzymes leading to low (potentially ineffective)or high (potentially toxic) levels of clozapine in the blood.  When used with these medications, the dose of clozapine may need to be reduced or increased.

Last Editorial Review: 2/8/2006

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