A Cochrane review [Abstract] 1 included 27 RCTs with a total of 3099 patients with schizophrenia. Clozapine was compared with olanzapine (12 trials), risperidone (9 trials), quetiapine (5 trials), zotepine (2 trials) and ziprasidone (1 trial). Twenty studies were short term (two up to 12 weeks), 5 studies reported data for up to 26 weeks, and only two reported data for more than 26 weeks. Fewer participants on clozapine left the trials early due to inefficacy than risperidone (RR 0.40, CI 0.23 to 0.70, NNT 11, CI 7 to 21; 6 trials, n=627), suggesting a certain higher efficacy of clozapine. Clozapine was more efficacious than zotepine in improving the participants' general mental state (BPRS total score: MD -6.00, CI -9.83 to -2.17; 1 trial, n=59), but not consistently more than olanzapine, quetiapine, risperidone and ziprasidone. There was no significant difference between clozapine and olanzapine or risperidone in terms of positive or negative symptoms of schizophrenia. According to studies from China quetiapine was more efficacious for negative symptoms than clozapine (MD 2.23, CI 0.99 to 3.48; 2 trials, n=142). Clozapine had a higher attrition rate due to adverse effects than olanzapine (RR 1.60, CI 1.07 to 2.40, NNT 25, CI 15 to 73; 9 trials, n=1674) and risperidone (RR 1.88, CI 1.11 to 3.21, NNT 16, CI 9 to 59; 6 trials, n=627). Clozapine produced somewhat fewer extrapyramidal side-effects than risperidone (use of antiparkinson medication: RR 0.39, CI 0.22 to 0.68, NNT 7, CI 5 to 18; 6 trials, n=304) and zotepine (RR 0.05, CI 0.00 to 0.86, NNT 3, CI 2 to 5; 1 trial, n=59). More participants in the clozapine group showed decreased white blood cells than those taking olanzapine, more hypersalivation and sedation than those on olanzapine, risperidone and quetiapine and more seizures than people on olanzapine and risperidone. Also, clozapine produced an important weight gain not seen with risperidone.
Comment: The quality of the evidence is downgraded by study quality (inadequate allocation concealment, lack of blinding, more than 20% loss to follow-up, short follow-up time) and imprecise results (limited study size for comparisons).
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