Clozapine versus typical neuroleptic medication for schizophrenia

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Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 02/2009; 1(1):CD000059. DOI: 10.1002/14651858.CD000059.pub2
Source: PubMed


Long-term drug treatment of schizophrenia with typical antipsychotics has limitations: 25 to 33% of patients have illnesses that are treatment-resistant. Clozapine is an antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment.
To evaluate the effects of clozapine compared with typical antipsychotic drugs in people with schizophrenia.
For the current update of this review (March 2006) we searched the Cochrane Schizophrenia Group Trials Register.
All relevant randomised clinical trials (RCTs).
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.
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.
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.

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    • "Clozapine is an atypical antipsychotic and is considered the most effective treatment for schizophrenia (Leucht et al., 2013). Due to its high risk of serious side effects and the need for clinical monitoring, it is only used in patients who are resistant or intolerant to other antipsychotic drugs (Essali et al., 2009; Meltzer, 2010; Fakra and Azorin, 2012). The exact pharmacological, morphological, and molecular mechanisms through which clozapine exerts its antipsychotic action are not fully understood . "
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    ABSTRACT: Clozapine is an atypical antipsychotic drug used in the treatment of schizophrenia, which has been shown to reverse behavioural and dendritic spine deficits in mice. It has recently been shown that deficiency of 14-3-3ζ has an association with schizophrenia, and that a mouse model lacking this protein displays several schizophrenia-like behavioural deficits. To test the effect of clozapine in this mouse model, 14-3-3ζ KO mice were administered clozapine (5mg/kg) for two weeks prior to being analysed in a test battery of cognition, anxiety, and despair (depression-like) behaviours. Following behavioural testing brain samples were collected for analysis of specific anatomical defects and dendritic spine formation. We found that clozapine reduced despair behaviour of 14-3-3ζ KO mice in the Forced Swim Test (FST) and altered the behaviour of wild types and 14-3-3ζ KO mice in the Y-maze task. In contrast, clozapine had no effects on hippocampal laminar defects or decreased dendritic spine density observed in 14-3-3ζ KO mice. Our results suggest that clozapine may have beneficial effects on clinical behaviours associated with deficiencies in the 14-3-3ζ molecular pathway, despite having no effects on morphological defects. These findings may provide mechanistic insight to the action of this drug.
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    • "Clozapine has shown to be more robustly and consistently superior to other antipsychotics (Leucht et al., 2013), particularly in patients with treatment-resistant schizophrenia (TRS) (Essali et al., 2009). Clozapine may induce agranulocytosis in rare cases (Idanpaan-Heikkila et al., 1975), therefore, it was removed from development or the market in the 1970s in the U.S. and many European countries. "
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    ABSTRACT: We examined the time trends and correlates of clozapine use in schizophrenia patients in China. A total of 14,013 patients with schizophrenia treated in 45 psychiatric hospitals/centers nationwide were interviewed in 2002, 2006 and 2012. Patients' socio-demographic and clinical characteristics including psychopathology, medication side effects, satisfaction with treatment and quality of life (QOL) were recorded in a standardized fashion. Clozapine was used in 32.9% of the whole sample; with corresponding figures of 39.7%, 32.5% and 26.4% in 2002, 2006 and 2012 (p<0.001). Families of clozapine users had lower satisfaction with treatment than those of the non-clozapine group, without significant differences with respect to patients' treatment satisfaction and mental or physical QOL. In multiple logistic regression analyses, compared to the non-clozapine group, patients on clozapine had an earlier age of onset, longer illness duration, more global illness severity and drug-induced central nervous system, gastrointestinal and other side effects, lower antipsychotic doses, less delusions and hallucinations, more negative symptoms, were more likely male, inpatients, to have a family history of psychiatric disorders, receive treatments in regional centers and receive antipsychotic polypharmacy, but less likely to have health insurance and receive first-generation antipsychotics and benzodiazepines (R(2)=0.498, p<0.001). Clozapine was used in one-third of schizophrenia patients in China, with decreasing frequency since 2002. Patients prescribed clozapine had multiple markers of greater global illness severity/chronicity and decreased satisfaction with treatment by the families, but similar QOL and less delusions and hallucinations than patients not prescribed clozapine. Copyright © 2015 Elsevier B.V. All rights reserved.
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    • "Treatment of patients with minimal or no response to adequate doses of antipsychotics represents an enormous challenge for clinicians. These antipsychotic-resistant patients constitute up to 25%–30% of all patients suffering from schizophrenia.2,4,5 One of the main reasons for this is our lack of understanding of the etiology of schizophrenia. "
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