Evidence-Based Reviews

Clozapine for schizophrenia: Life-threatening or life-saving treatment?

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Clozapine, despite its side effect burden, may be the most effective and have the lowest mortality risk among all available antipsychotics



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Researchers in Finland surprised psychiatrists this year by announcing that clozapine “seems to be associated with a substantially lower mortality than any other antipsychotic.”1 This finding also surprised the researchers, who expected their 11-year study to link long-term use of second-generation (“atypical”) antipsychotics with increased mortality in patients with schizophrenia. Instead they found longer lives in patients who used antipsychotics (and particularly clozapine), compared with no antipsychotic use.

This study’s findings do not change clozapine’s association with potentially fatal agranulocytosis as well as weight gain, metabolic abnormalities, and other adverse effects. Clozapine also is difficult to administer ( Box 1 ),2 and patients must be enrolled in FDA-mandated registries (see Related Resources ). These obstacles might discourage you from offering clozapine to patients who could benefit from it ( Box 2 ).3-5

Why bother considering clozapine? Because recent data on decreased mortality, decreased suicidality, and control of aggressive behavior make clozapine a compelling choice for many patients. Careful attention to clozapine’s adverse effect profile is necessary, but you can manage these risks with appropriate monitoring.

Box 1

How to meet FDA mandates for administering clozapine

Because of clozapine’s risk for leukopenia and agranulocytosis, frequent white blood cell count (WBC) monitoring is required. The risk of drug-induced blood dyscrasias has been shown to decrease over time, however, from 0.70/1,000 patient-years in the second 6 months of treatment to 0.39/1,000 patient-years after the first year.2

To start clozapine treatment, FDA guidelines require that the patient’s WBC must be at least 3,500 mm3, and the absolute neutrophil count (ANC) must be at least 2,000 mm3. For the first 6 months, patients receiving clozapine must have a weekly blood test for WBC and ANC.

The dispensing pharmacist must see the blood work result prior to releasing the drug to the patient. The blood draw date must be within the previous 7 days for the pharmacist to dispense a 1-week supply of clozapine.

Decreased monitoring over time. After 6 months of continuous therapy with clozapine without any interruptions because of a low WBC and/or ANC—defined as WBC 3 and/or ANC 3 or increased monitoring (when WBC 3 and/or ANC 3)—the patient’s blood monitoring may be done every 14 days and a 2-week supply of clozapine can be dispensed.

After 12 months of continuous clozapine therapy—6 months of continuous weekly monitoring, then 6 months of continuous biweekly monitoring—without any interruptions or increased monitoring, the patient may have blood monitoring done every 4 weeks and can receive a 4-week supply of clozapine.

One advantage of these monitoring requirements is that the increased frequency of visits can be used to foster greater patient engagement with treatment and promote a therapeutic alliance. Peer-led clozapine support groups, available in some communities, can facilitate adherence to monitoring requirements.

Box 2

Clozapine’s indications, dosing, and use in clinical practice

Clozapine was approved in the United States in 1989 for severely ill patients with schizophrenia who had not responded adequately to standard drug treatment. In 2002 it received an indication for patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.

Off-label, clozapine has been commonly used for refractory bipolar disorder. Since 1998, it has been available in generic formulations and in a proprietary orally-disintegrating tablet formulation.

Dosing. The recommended target clozapine dosage is 300 to 450 mg/d. If an adequate response is not achieved, obtaining a plasma level might be helpful.3 Plasma levels ≥350 ng/mL constitute an optimal clozapine trial.

Not a ‘last resort.’ American Psychiatric Association treatment guidelines for schizophrenia state: “Because of clozapine’s superior efficacy, a trial of clozapine should be considered for a patient with a clinically inadequate response to antipsychotic treatment or for a patient with suicidal ideation or behavior. Besides clozapine, there are limited options for the many patients who have severe and significant residual symptoms even after antipsychotic monotherapy has been optimized, and none have proven benefits.”4

As additional evidence accumulates—including benefits regarding mortality and aggression—clozapine’s advantages support its clinical use earlier than as a “last resort.” In institutional settings, clozapine use has increased with the availability of additional data, such as from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).

In New York State Office of Mental Health hospitals, clozapine use increased from 20.6% of prescriptions in 2005 to 24.9% in 2007, compared with the other CATIE medications (olanzapine, quetiapine, risperidone, ziprasidone) and haloperidol.5 Whether clozapine use will increase in outpatient settings remains to be seen.


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