Clozapine: A Fresh Look

Clozapine - antipsychotic for schizophreniaSeveral trials show it to be a superior treatment option, yet clozapine remains the “red-headed stepchild” of antipsychotics. Even though large studies reveal clozapine has impressive efficacy, particularly with treatment-resistant schizophrenia, many of us are reluctant to use it.

According to one study, of the 30% of patients who have treatment-resistant schizophrenia, just 5% are put on clozapine (Olfson M et al, Psychiatr Serv 2016;67(2):152). And, before turning to clozapine, some psychiatrists will try a dozen other atypical antipsychotics and antipsychotic polypharmacy.

So, why is there reluctance to prescribe this highly-effective antipsychotic?

There’s likely more than one reason. Many of us are justifiably concerned about clozapine’s serious potential side effects, which can include neutropenia, myocarditis, seizure, fecal impaction, and cardiomyopathy. We may also hesitate to choose clozapine because of the extra time and perceived inconvenience involved in lab monitoring, patient education, and extra required training (REMS certification) for prescribers.

For those reluctant to make clozapine their go-to antipsychotic for certain patients, this article will provide information to help you decide when it’s right to prescribe.

How effective is clozapine?

In 1989, clozapine—which is also marketed as Clozaril—was the first FDA-approved atypical antipsychotic for schizophrenia. It is indicated for
treatment-resistant schizophrenia, and for reducing the risk of suicide in patients with schizophrenia and schizoaffective disorder.

But is clozapine really more effective than other antipsychotics? Clozapine was first shown to be superior to chlorpromazine (Thorazine) in patients who had inadequate response to at least 3 first-generation antipsychotics (Kane J et al, Arch Gen Psych 1988;45(9):789– 796). At the end of 6 weeks, 30% of patients randomly assigned to clozapine (n = 126) responded, as opposed to only 4% of those randomized to chlorpromazine (n = 142). That’s a large difference, and since then other trials have gone on to report clozapine’s superiority in treatment-resistant schizophrenia compared with other antipsychotics, such as haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone. In addition, large effectiveness trials and population-based registry studies have demonstrated clozapine’s superior efficacy and increased patient adherence compared with both FGAs and SGAs.

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Clozapine is one of only a few drugs proven to decrease suicide risk. In a 2-year randomized controlled trial comparing clozapine with olanzapine (Zyprexa), clozapine was shown to significantly decrease suicide attempts, hospitalizations due to suicide, and suicide prevention treatment and interventions (Meltzer HY et al, Am J Psychiatry 2003;60(1):82–91).

Which patients are right for clozapine?

All treatment guidelines for schizophrenia recommend clozapine after inadequate response to at least 2 antipsychotics. For patients who are extremely aggressive or suicidal, the APA treatment guidelines state a trial of clozapine may be reasonable as a first- or second-line antipsychotic.

How to prescribe clozapine

Educate your patients. The first step is achieving buy-in from your patient and the family. You’ll need to give adequate disclosure about potential side effects, but this doesn’t have to be a long speech.

Introduce the use of clozapine with a discussion about how other medications haven’t been completely effective. Tell patients, “I know the medications you’ve tried haven’t completely helped you. Clozapine is a medication that is more effective for people when other antipsychotics haven’t worked. It has a bunch of side effects, but we can monitor for them. Should we try it for a little while? If it works, I think you might decide that the side effects are worth putting up with.”  Then, review the specific side effects and monitoring process.

Clozapine: A Fresh Look

This article originally appeared in:

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This article was published in print March 2018 in Volume:Issue 16:3.

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APA Reference
Psychiatry Report, T. (2019). Clozapine: A Fresh Look. Psych Central. Retrieved on September 19, 2020, from


Scientifically Reviewed
Last updated: 29 Apr 2019
Last reviewed: By John M. Grohol, Psy.D. on 29 Apr 2019
Published on All rights reserved.