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

• attempted suicide (34 vs 55)
  
• required hospitalization (82 vs 107) or rescue interventions to prevent suicide (118 vs 155)
  
• required concomitant treatment with antidepressants (221 vs 258) or anxiolytics/soporifics (301 vs 331).
  

The number needed to treat (NNT) to prevent 1 additional suicide attempt or 1 hospitalization to prevent suicide was 13 in favor of clozapine vs olanzapine. This means that for every 13 at-risk patients treated with clozapine instead of olanzapine, 1 suicide attempt or 1 hospitalization to prevent suicide would be prevented. (For more information about NNT, see Related Resources .)

More deaths from suicide occurred in the clozapine group than the olanzapine group, but the numbers were small (5 vs 3) and the difference between clozapine and olanzapine on this outcome was not statistically significant (P=.73).

Recommendation. Clozapine is a first-line treatment for patients with schizophrenia or schizoaffective disorder who exhibit suicidal behavior. This is reflected in the drug’s product labeling.

Superior symptom management

CATIE findings. Phase 2 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed clozapine to be more effective than other atypical antipsychotics, as measured by time to all-cause discontinuation.⁸ Patients in this phase of CATIE had discontinued another atypical antipsychotic in phase 1, principally because of lack of adequate efficacy. In phase 2, they were re-randomized to receive open-label clozapine or double-blinded risperidone, olanzapine, or quetiapine.

Only 90 patients were included in the time-to-discontinuation analysis, yet the greater amount of time that patients remained on clozapine (median 10.5 months) compared with quetiapine (median 3.3 months) or risperidone (median 2.8 months) was statistically significant. Time to discontinuation because of inadequate therapeutic effect also was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone.

The NNT for the outcome of all-cause discontinuation for clozapine was 4 compared with risperidone and 3 compared with quetiapine. This means for every 4 or 3 patients randomly assigned to clozapine instead of risperidone or quetiapine, respectively, 1 additional patient successfully completed the CATIE trial on the original phase 2 medication.⁹ The NNT for clozapine vs olanzapine was 7, indicating a respectable effect size difference that might have been statistically significant if the sample size had been larger.

Meta-analyses support CATIE results. Clozapine’s greater efficacy (and effectiveness) compared with other antipsychotics as demonstrated in CATIE is supported by 2 meta-analyses:

• A systematic review of clinical trials between January 1953 and May 2002 found clozapine’s effect size in reducing symptoms for patients with schizophrenia was greater than that of any other antipsychotic.¹⁰
  
• In a similar but more recent meta-analysis of 150 double-blind, mostly short-term studies totaling 21,533 participants, clozapine showed the largest effect size when atypical antipsychotics were compared with first-generation antipsychotics.¹¹
  

Finally, a meta-analysis of data from randomized trials comparing ≥2 atypical antipsychotics (78 studies; 13,558 total participants)¹² demonstrates the importance of providing therapeutic dosing of clozapine. Most of the studies used low clozapine dosages (such as 400 mg/d).

Caveats about clozapine

First-episode schizophrenia. Clozapine has been shown to be more effective than chlorpromazine in terms of time to remission and maintenance of remission for treatment-naïve patients with first-episode schizophrenia.¹³ Even so, most clinicians probably would not consider clozapine as a first-line treatment for an uncomplicated first-episode patient because of concerns about agranulocytosis. When genetic testing becomes available to determine individual risk for agranulocytosis, perhaps clozapine will be used earlier in the disease course.¹⁴

Titration and monitoring. Slow and careful titration of clozapine is necessary, making it less than ideal if rapid control of acute psychotic symptoms is required. In terms of monitoring for adverse effects, clozapine’s product information carries “black box” warnings about the risk of agranulocytosis, seizures, myocarditis, orthostatic hypotension, and increased mortality in elderly patients with dementia-related psychosis. Common side effects include hypersalivation, excessive sedation, weight gain/metabolic abnormalities, tachycardia, dizziness, and constipation ( Table ).
The patient’s ethnicity may influence the risk of adverse effects, as observed in the study examining clozapine’s antiaggressive effect;⁶ African-American patients receiving antipsychotics—and particularly clozapine—may be more likely to develop metabolic abnormalities than patients in other ethnic groups.¹⁵ Carefully monitor all patients receiving clozapine for metabolic adverse effects, and be prepared to institute remediative psychosocial, lifestyle, and adjunctive medication interventions, such as statins.