All relevant randomised clinical trials (RCTs).
DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model.
MAIN RESULTS: We have included 42 trials (3950 participants) in this review. Twenty-eight of the included studies are less than 13 weeks in duration, and, overall, trials were at significant risk of bias. We found no significant difference in the effects of
clozapine and typical
neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at the end of the study. Clinical improvements were seen more frequently in those taking
clozapine (n=1119, 14 RCTs, RR 0.72 CI 0.7 to 0.8, NNT 6 CI 5 to 8). Also, participants given
clozapine had fewer relapses than those on typical
antipsychotic drugs (n=1303, RR 0.62 CI 0.5 to 0.8, NNT 21 CI 15 to 49). BPRS scores showed a greater reduction of symptoms in
clozapine-treated patients, (n=1145, 16 RCTs, WMD -4.22 CI -5.4 to -3.1), although the data were heterogeneous (Chi(2) 0.0001, I(2) 66%). Short-term data from the SANS negative symptom scores favoured
clozapine (n=196, 5 RCTs, WMD -5.92 CI -7.8 to -4.1). We found
clozapine to be more acceptable in long-term treatment than conventional
antipsychotic drugs (n=982, 16 RCTs, RR 0.60 CI 0.5 to 0.7, NNT 15 CI 12 to 20). Blood problems occurred more frequently in participants receiving
clozapine (3.2%) compared with those given typical
antipsychotics (0%) (n=1031, 13 RCTs, RR 7.09 CI 2.0 to 25.6).
Clozapine participants experienced more drowsiness,
hypersalivation, or temperature increase, than those given conventional
neuroleptics. However,
clozapine patients experienced fewer motor adverse effects (n=1433, 18 RCTs, RR 0.58 CI 0.5 to 0.7, NNT 5
CI 4 to 6).The clinical effects of
clozapine were more pronounced in participants resistant to typical
neuroleptics in terms of clinical improvement (n=370, 4 RCTs, RR 0.71 CI 0.6 to 0.8, NNT 4 CI 3 to 6) and symptom reduction. Thirty-four per cent of treatment-resistant participants had a clinical improvement with
clozapine treatment.
AUTHORS' CONCLUSIONS:
Clozapine may be more effective in reducing symptoms of
schizophrenia, producing clinically meaningful improvements and postponing relapse, than typical
antipsychotic drugs - but data are weak and prone to bias. Participants were more satisfied with
clozapine treatment than with typical
neuroleptic treatment. The clinical effect of
clozapine, however, is, at least in the short term, not reflected in measures of global functioning such as ability to leave the hospital and maintain an occupation. The short-term benefits of
clozapine have to be weighed against the risk of adverse effects. Within the context of trials, the potentially dangerous white blood cell decline seems to be more frequent in children and adolescents and in the elderly than in young adults or people of middle-age.The existing trials have largely neglected to assess the views of participants and their families on
clozapine. More community-based long-term randomised trials are needed to evaluate the efficacy of
clozapine on global and social functioning as trials in special groups such as people with
learning disabilities.