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Effectiveness of Clozapine versus Other Atypical Antipsychotics: Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) 

Effectiveness of Clozapine versus Other Atypical Antipsychotics: Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE)
Effectiveness of Clozapine versus Other Atypical Antipsychotics: Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE)

Eunice Yuen

, and Cenk Tek

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For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine’s serious side effects.

The CATIE Investigators1

Research Question:

What is the role of clozapine among patients with chronic schizophrenia who fail to respond to atypical antipsychotics?


The National Institute of Mental Health

Year Study Began:


Year Study Published:


Study Location:

57 sites in the United States in inpatient and outpatient settings at universities, state facilities, Virginia hospitals, private agencies, private practice, and mixed system sites.2

Who Was Studied:

Adults 18 to 65 years old with a DSM-IV diagnosis of schizophrenia who could take oral antipsychotic medication. A broad spectrum of patients with schizophrenia were enrolled, including outpatients who remained symptomatic or continued to suffer from medication side effects, as well as inpatients who had acute exacerbation.3

Who Was Excluded:

Patients that presented with first-episode psychosis and prior history of treatment resistance to antipsychotics. Also excluded were those who were pregnant or breast-feeding during the time of treatment, as well as those who were medically unstable.

How Many Participants:

1,493 in CATIE; 99 in this particular study.

Study Overview:

See Figure 41.1 for a summary of the study design.

Figure 41.1 Summary of Study Design

Figure 41.1 Summary of Study Design

aPatients with tardive dyskinesia at baseline were excluded from random assignment of perphenazine in phase 1.

bSubjects were not randomized to medications they had previously been given in the study.3

Study Intervention:

First, patients were randomized to receive treatment with either an atypical antipsychotic (olanzapine, quetiapine, risperidone, or ziprasidone) or a typical antipsychotic (perphenazine). Those randomized to receive perphenazine whose treatment was discontinued for any reason were then randomized to receive olanzapine, quetiapine, or risperidone. The subjects were randomized further to various antipsychotics as indicated in Figure 41.1.

In the clozapine group, titration and maintenance dosing schedules were determined by physicians based on closely monitoring on patient’s agranulocytosis and myocardial inflammation. Standard weekly white cell count, sedimentation rate, and creatine phosphokinase levels were performed. Moreover, electrocardiograms were performed prior to and at week 1, 2, and 4 weeks after treatment.

For subjects assigned to the newer atypical antipsychotics, dosing was initiated at one capsule a day of olanzapine (7.5 mg), quetiapine (200 mg), or risperidone (1.5 mg). Titration dosing schedules were adjusted by clinicians up to four capsules per day.

Decisions of treatment discontinuation were based on therapeutic effect, side effects, and patient preference.


18 months


The primary outcome measure was the time until treatment discontinuation due to tolerability and efficacy. Secondary outcome measures included the reasons for treatment discontinuation, including side effects, inefficacy, or patient preference. The Positive and Negative Syndrome Scale (PANSS) was used to measure clinical symptoms and the Clinical Global Impression (CGI) was used to assess illness severity.


  • Patients treated with clozapine had a significantly longer time before treatment discontinuation compared to those treated with quetiapine or risperidone. There was also a nonsignificant trend toward longer time before treatment discontinuation among patients treated with clozapine versus olanzapine.

  • Clinical symptoms measured by PANSS were significantly improved among patients receiving clozapine compared to those receiving quetiapine or risperidone, though there was no difference relative to those receiving olanzapine. Clozapine-treated patients also had significant improvement in CGI severity at three months compared to the groups treated with olanzapine and quetiapine, though not risperidone.

  • Clozapine had a distinct side effect profile compared to the other atypical antipsychotics. Clozapine was less associated with insomnia, elevated prolactin, and anti-cholinergic symptoms (dry mouth, urinary hesitancy, and constipation). Out of the 49 patients treated with clozapine, one developed agranulocytosis and another developed eosinophilia (Table 41.1).

Table 41.1 Summary of CATIE: Clozapine versus Other Atypical Antipsychotics Key Findings




P Value


P Value


P value

Median time to treatment discontinuation in months (95% CI)

10.5 (7.3–16.1)

2.7 (1.9–11.9)

3.3 (1.0–4.9)

2.8 (1.1–4.0)

Hazard ratio compared to clozapine for treatment discontinuation








Hazard ratio compared to clozapine due to lack of efficacy








note: CATIE = Clinical Antipsychotic Trials for Interventions Effectiveness.

Criticisms and Limitations:

Unlike other antipsychotics given as blinded treatment, clozapine was administered in an open-label manner. Many clinicians view clozapine as the last resort medication. This perception could have influenced the study results.

While the entire CATIE trial had almost 1,500 patients, this study only utilized 99 patients. This relatively small sample size may not offer adequate power for reasonable comparisons across different atypical antipsychotics.

Other Relevant Studies and Information:

  • A number of other studies comparing clozapine to alternative psychotics typically used in treating schizophrenia have come to similar conclusions as CATIE.4,5,6

  • A follow-up study to CATIE found that risperidone and olanzapine are more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation.7

  • Another study suggests that in patients with treatment resistance to olanzapine, 41% of this population shows significant respond to clozapine.8

  • Another recent study utilizing patients from the CATIE trial suggests that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia.9

  • International Suicide Prevention Trial (InterSePT) suggests that clozapine is significantly more effective in suicidal prevention than olanzapine for patients with schizophrenia and schizoaffective disorder.10

  • Longitudinal cohort study suggests that patients taking clozapine have the lowest morality rate among second generation antipsychotics.11

  • American Psychiatric Association (APA) treatment guidelines recommend the use of clozapine when there is an inadequate response to other antipsychotic medications or when a patient has persistent suicidal ideation.12 Clozapine is considered a second-line agent due to its unfavorable side effect profile.

Summary and Implications:

The CATIE trial investigated strategies to treat patients with chronic schizophrenia unresponsive to initial therapy with antipsychotics. The study found that switching to clozapine as compared to other atypical antipsychotics was significantly more effective. However, because clozapine may cause several side effects that warrant close monitoring, including agranulocytosis, myocarditis, seizure, diabetes, and other metabolic abnormalities, guidelines from the APA recommend that clozapine should be considered only among patients with an inadequate response to antipsychotic medications or those with persistent suicidal ideation.12

Clinical Case: Effectiveness of Clozaphine Versus Other Atypical Antipsychotics in Patients with Chronic Schizophrenia

Case History

A 40-year-old man with a history of schizophrenia is admitted to the inpatient psychiatric ward for worsening bizarre behavior. On the unit, he is observed screaming at the microwave and told staff that he was worried that the machine could read his thoughts. He denies any mood symptoms and history of drug use. He does not have other active medical problems. Despite the patient’s compliance with taking quetiapine (400 mg) twice per day for the past 6 months, he has not shown significant improvement. The patient recently decided to self-discontinue the medication for lack of efficacy. He has not noticed any significant side effects from quetiapine.

Based on the results of CATIE, how should this patient be treated?

Suggested Answer

CATIE found that for patients who do not respond to atypical antipsychotics, clozapine is superior to another atypical antipsychotics in terms of prolonging the time to stay on treatment and improving positive and negative symptomatology. Clozapine has been associated with significant side effects, so it is important to carefully weigh the risks and benefits of starting clozapine in any patient.

The patient in this vignette is typical of patients included in CATIE trial. Thus, he and the doctor should consider switching to clozapine. Fortunately, the patient does not have any significant side effects from quetiapine. If clozapine is started, the patient would need weekly blood draws for the first 6 months, biweekly thereafter, and be seen in clinic frequently to monitor for any side effects.


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