We selected trials and extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD) again based on a random-effects model.
MAIN RESULTS: The review currently includes 27 blinded randomised controlled trials, which involved 3099 participants. Twelve randomised control trials compared
clozapine with
olanzapine, five with
quetiapine, nine with
risperidone, one with
ziprasidone and two with
zotepine. Attrition from these studies was high (overall 30.1%), leaving the interpretation of results problematic.
Clozapine had a higher attrition rate due to adverse effects than
olanzapine (9 RCTs, n=1674, RR 1.60 CI 1.07 to 2.40, NNT 25 CI 15 to 73) and
risperidone (6 RCTs, n=627, RR 1.88 CI 1.11 to 3.21, NNT 16 CI 9 to 59). Fewer participants in the
clozapine groups left the trials early due to inefficacy than
risperidone (6 RCTs, n=627, RR 0.40 CI 0.23 to 0.70, NNT 11 CI 7 to 21), suggesting a certain higher efficacy of
clozapine.Clozapine was more efficacious than
zotepine in improving the participants general mental state (BPRS total score: 1 RCT, n=59, MD -6.00 CI -9.83 to -2.17), 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 two studies from China
quetiapine was more efficacious for negative symptoms than
clozapine (2 RCTs, n=142, MD 2.23 CI 0.99 to 3.48).
Clozapine produced somewhat fewer extrapyramidal side-effects than
risperidone (use of antiparkinson medication: 6 RCTs, n=304, RR 0.39 CI 0.22 to 0.68, NNT 7 CI 5 to 18) and
zotepine (n=59, RR 0.05 CI 0.00 to 0.86, NNT 3 CI 2 to 5). 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.Other differences in adverse effects were less documented and should be replicated, for example,
clozapine did not alter
prolactin levels whereas
olanzapine,
risperidone and
zotepine did; compared with
quetiapine,
clozapine produced a higher incidence of electrocardiogram (ECG) alterations; and compared with
quetiapine and
risperidone clozapine produced a higher increase of
triglyceride levels. Other findings that should be replicated were:
clozapine improved social functioning less than
risperidone and fewer participants in the
clozapine group had to be hospitalised to avoid suicide attempts compared to
olanzapine.Other important outcomes such as service use, cognitive functioning, satisfaction with care or quality of life were rarely reported.
AUTHORS' CONCLUSIONS:
Clozapine may be a little more efficacious than
zotepine and
risperidone but further trials are required to confirm this finding.
Clozapine differs more clearly in adverse effects from other second generation
antipsychotics and the side-effect profile could be key in the selection of treatment depending on the clinical situation and a patient's preferences. Data on other important outcomes such as cognitive functioning, quality of life, death or service use are currently largely missing, making further large and well-designed trials necessary. It is also important to take into account that the large number of people leaving the studies early limits the validity and interpretation of our findings.