***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: This 18-week , r and omized , flexible-dose , double-blind , double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients . Patients had a DSM-IV diagnosis of schizophrenia , a history of resistance and /or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses , PANSS score > or=80 , and CGI-S score > or=4 . Patients were r and omized to ziprasidone ( 80 - 160 mg/day , n=73 ) or clozapine ( 250 - 600 mg/day , n=74 ) . On the primary ITT-LOCF analysis , baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone ( -25.0+/-22.0 , 95 % CI -30.2 to -19.8 ) and clozapine ( -24.5+/-22.5 , 95 % CI -29.7 to -19.2 ) groups . A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms . There were also significant improvements on PANSS subscales , CGI-S , CG-I , CDSS , and GAF , without between-drug differences . The two treatment groups had similar rates of early discontinuations due to AEs . AEs were mostly of similar mild-moderate severity in the two groups . There were also no detrimental effects on prolactin , renal and liver function , hematology , and cardiovascular parameters . However , ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores . Moreover , when compared with clozapine , ziprasidone also had a more favorable metabolic profile , with significant endpoint differences in weight , fasting glucose , total cholesterol , LDL cholesterol , and triglycerides . In conclusion , this trial indicates that both ziprasidone and clozapine , having comparable efficacy coupled with satisfactory general safety and tolerability , may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and /or intolerance to antipsychotics . The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians , at least in the presence of patients at high risk for metabolic disorders OBJECTIVE This prospect i ve , double-blind , multicenter , parallel-group study compared the efficacy and safety of therapeutic doses of clozapine and risperidone in patients with severe chronic schizophrenia and poor previous treatment response . METHOD Male or female patients aged 18 - 65 years who met DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response ( N=273 ) were r and omly assigned to double-blind treatment with either clozapine or risperidone administered over 12 weeks in increasing increments . The primary efficacy measures were the magnitude of improvement in Brief Psychiatric Rating Scale ( BPRS ) and Clinical Global Impression ( CGI ) scores . Adverse events were recorded throughout the study . RESULTS The magnitude of improvement in mean BPRS and CGI scores from baseline to end of the study was significantly greater in the clozapine group than in the risperidone group . Statistically significant differences in favor of clozapine were also seen for most of the secondary efficacy measures ( Positive and Negative Syndrome Scale , Calgary Depression Scale , Psychotic Depression Scale , and Psychotic Anxiety Scale ) . The adverse event profile was similar for both treatment groups , with a lower risk of extrapyramidal symptoms in the clozapine group . CONCLUSIONS Clozapine showed superior efficacy over risperidone in this patient population . Both treatments were equally well tolerated as demonstrated through their adverse event profiles , although as expected clozapine was associated with a lower risk of extrapyramidal symptoms than risperidone OBJECTIVE When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug  , it is unclear what other antipsychotic to switch to and when to use clozapine . In this study , the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness ( CATIE ) investigation . METHOD Ninety-nine patients who discontinued treatment with olanzapine , quetiapine , risperidone , or ziprasidone in phase 1 or 1B of the trials , primarily because of inadequate efficacy , were r and omly assigned to open-label treatment with clozapine ( N=49 ) or blinded treatment with another newer atypical antipsychotic not previously received in the trial ( olanzapine [ N=19 ] , quetiapine [ N=15 ] , or risperidone [ N=16 ] ) . RESULTS Time until treatment discontinuation for any reason was significantly longer for clozapine ( median=10.5 months ) than for quetiapine ( median=3.3 ) , or risperidone ( median=2.8 ) , but not for olanzapine ( median=2.7 ) . Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine , quetiapine , or risperidone . At 3-month assessment s , Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine . One patient treated with clozapine developed agranulocytosis , and another developed eosinophilia ; both required treatment discontinuation . CONCLUSIONS For these patients with schizophrenia who prospect ively failed to improve with an atypical antipsychotic , clozapine was more effective than switching to another newer atypical antipsychotic . Safety monitoring is necessary to detect and manage clozapine 's serious side effects BACKGROUND Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant . The psychiatrist has a limited evidence base to guide treatment , particularly as there are no trials in children comparing atypical antipsychotics , the mainstay of current treatment . OBJECTIVE To compare the efficacy and safety of olanzapine and clozapine , hypothesizing that clozapine would be more efficacious . DESIGN Double-blind r and omized 8-week controlled trial , with a 2-year open-label follow-up . SETTING National Institute of Mental Health study , January 1998 to June 2005 . Patients underwent re assessment 2 years after discharge . PATIENTS Children and adolescents recruited nationally , aged 7 to 16 years , meeting unmodified DSM-IV criteria for schizophrenia , and resistant to treatment with at least 2 antipsychotics . INTERVENTIONS After drug washout and a 1- to 3-week antipsychotic-free period , patients were r and omized to treatment with clozapine ( n = 12 ) or olanzapine ( n = 13 ) . MAIN OUTCOME MEASURES The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms . RESULTS Clozapine was associated with a significant reduction in all outcome measures , whereas olanzapine showed a less consistent profile of clinical improvement . While there were moderate to large differential treatment effects in favor of clozapine , these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline ( P = .04 ; effect size , 0.89 ) . Clozapine was associated with more overall adverse events . At 2-year follow-up , 15 patients were receiving clozapine with evidence of sustained clinical improvement , but additional adverse events emerged , including lipid anomalies ( n = 6 ) and seizures ( n = 1 ) . CONCLUSIONS While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia , the study suggests that clozapine has a more favorable profile of clinical response , which is balanced against more associated adverse events OBJECTIVE The authors compared the efficacy and safety of three atypical antipsychotics ( clozapine , olanzapine , and risperidone ) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder . METHOD In a double-blind trial , 157 in patients with a history of suboptimal treatment response were r and omly assigned to treatment with clozapine , olanzapine , risperidone , or haloperidol for 14 weeks ( an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period ) . RESULTS Clozapine , risperidone , and olanzapine ( but not haloperidol ) result ed in statistically significant improvements in total score on the Positive and Negative Syndrome Scale . Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol . The atypical drugs , particularly olanzapine and clozapine , were associated with weight gain . CONCLUSIONS The effects of atypical antipsychotics in this population were statistically significant but clinical ly modest . The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective . Clozapine was the most effective treatment for negative symptoms . However , the differences among treatments were small BACKGROUND Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia , questions remain regarding its efficacy for primary negative symptoms , comparison with a moderate dose of a first-generation antipsychotic , and adverse effects during a longer-term trial . This study examined its efficacy in partially responsive , community-based patients , compared clozapine with moderate-dose haloperidol , and extended treatment to 6 months . METHODS R and omized , double-blind , 29-week trial comparing clozapine  ( n = 37 ) with haloperidol  ( n = 34 ) . Subjects with schizophrenia who were being treated in community setting s at 3 collaborating clinical facilities were enrolled . RESULTS Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy ( 51 % ) than were those treated with clozapine ( 12 % ) . A higher proportion of clozapine-treated subjects met an a priori criterion of improvement ( 57 % ) compared with haloperidol-treated subjects ( 25 % ) . Significantly greater improvement was seen in symptoms of psychosis , hostile-suspiciousness , anxiety-depression , thought disturbance , and total score measured on the Brief Psychiatric Rating Scale . No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms . Subjects treated with clozapine experienced more excess salivation , dizziness , and sweating and less dry mouth and decreased appetite than those treated with haloperidol . CONCLUSIONS Compared with a first-generation antipsychotic given in a moderate dose , clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community . Advantages are seen in a broad range of symptoms but do not extend to negative symptoms BACKGROUND The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge . Clozapine has been one treatment option ; however , it is not universally effective and is limited in its use by safety concerns . With the introduction of newer agents , their performance relative to clozapine is of great clinical interest . METHODS The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients . The study was primarily design ed to demonstrate the " noninferiority " of olanzapine compared to clozapine after 18 weeks of double-blind treatment . Conclusions were based on the one-sided lower 95 % confidence limit about the treatment effect observed from the primary efficacy variable ( Positive and Negative Syndrome Scale [ PANSS ] Total ) . RESULTS Mean changes from baseline to end point in PANSS Total score , using a last observation carried forward technique , showed that both agents were comparably effective in neuroleptic resistant patients , i.e. , demonstrated the " noninferiority " of olanzapine when compared to clozapine . Overall , significantly fewer olanzapine-treated patients ( 4 % ) discontinued for an adverse event than their clozapine-treated ( 14 % ) counterparts ( p = .022 ) . Among spontaneously reported adverse events , increased salivation , constipation , dizziness , and nausea were reported significantly more often among clozapine-treated patients , whereas only dry mouth was reported more often among olanzapine-treated patients . CONCLUSIONS Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant schizophrenic patients clinical ly eligible for treatment with clozapine The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge . Clozapine , an atypical antipsychotic drug , has long been of scientific interest , but its clinical development has been delayed because of an associated risk of agranulocytosis . This report describes a multicenter clinical trial to assess clozapine 's efficacy in the treatment of patients who are refractory to neuroleptics 
    Output:
    
These reductions are clinical ly meaningful .