***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: BACKGROUND Few controlled studies have compared the efficacy of clozapine and risperidone in treatment-refractory schizophrenic patients . The present study investigates the efficacy of both clozapine and risperidone on psychopathologic and neurocognitive measures in a prospect i ve 12-week open-label trial in treatment-refractory schizophrenic patients from state psychiatric hospitals . METHOD Thirty-five DSM-IV schizophrenic patients with a documented history of nonresponse to typical neuroleptics were treated with either clozapine or risperidone . Response was assessed every 2 weeks by independent raters with the Positive and Negative Syndrome Scale ( PANSS ) , the Clinical Global Impressions ( CGI ) scale , neurologic rating scales , and plasma drug levels . Neurocognitive tests were administered at baseline and week 12 . RESULTS Both clozapine and risperidone brought about significant ( p < .003 ) overall improvement in psychopathology . However , clozapine was numerically superior to risperidone on PANSS total scores and PANSS positive , negative , excitement , and cognitive factors . Extrapyramidal side effects were minimal for clozapine , whereas some were present for risperidone . Patients taking risperidone improved significantly in the beginning stages of the study and remained stable thereafter . Patients taking clozapine showed a gradual improvement that occurred over the entire length of the trial . Neurocognitive measures showed minimal improvement and did not differentiate between the 2 medication groups . CONCLUSION Both clozapine and risperidone were comparably effective across a wide spectrum of psychopathologic measures . While the efficacy of clozapine was only numerically superior to that of risperidone , it was associated with fewer extrapyramidal side effects and with progressive improvement over the 12-week treatment period , suggesting that in longer trials clozapine may prove to be superior to risperidone in neuroleptic-refractory patients 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 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 The data for medical decision analyses are often unreliable . Traditional sensitivity analysis --varying one or more probability or utility estimates from baseline values to see if the optimal strategy changes -- is cumbersome if more than two values are allowed to vary concurrently . This paper describes a practical method for probabilistic sensitivity analysis , in which uncertainties in all values are considered simultaneously . The uncertainty in each probability and utility is assumed to possess a probability distribution . For ease of application we have used a parametric model that permits each distribution to be specified by two values : the baseline estimate and a bound ( upper or lower ) of the 95 percent confidence interval . Following multiple simulations of the decision tree in which each probability and utility is r and omly assigned a value within its distribution , the following results are recorded : ( a ) the mean and st and ard deviation of the expected utility of each strategy ; ( b ) the frequency with which each strategy is optimal ; ( c ) the frequency with which each strategy " buys " or " costs " a specified amount of utility relative to the remaining strategies . As illustrated by an application to a previously published decision analysis , this technique is easy to use and can be a valuable addition to the armamentarium of the decision analyst We examined the response to clozapine in 10 schizophrenic patients who had been followed prospect ively from the time of their first hospitalization and who were refractory to multiple clinical trials with typical Clozapine is the only antipsychotic in the United States that has been approved by the Food and Drug Administration ( FDA ) for treatment-resistant schizophrenia . It provides effective treatment even when patients do not respond to other secondgeneration antipsychotics . [ 1 ] It also remains the most effective antipsychotic available . No existing first or second-generation antipsychotic has been consistently found to be as effective as clozapine monotherapy in treatment-resistant patients . [ 2 - 6 ] Among patients who entered Phase 2 of the Clinical Antipsychotic Trial of Intervention Effectiveness ( CATIE ) because of lack of efficacy in Phase 1 of the study , those treated with clozapine ( open label ) averaged significantly greater time to treatment discontinuation ( 10.5 months ) compared to patients treated with other antipsychotic medications ( 2.7 - 3.3 months ) . At three months , total symptom scores also improved to a significantly greater degree in the clozapine group compared to those treated with risperidone or quetiapine . [ 7 ] Similarly , in the open-label , r and omized CUtLASS ( Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study ) trial , clozapine treatment was associated with significantly greater improvement in total scores of the Positive and Negative Symptom Scale ( PANSS ) and better patient subjective ratings compared to risperidone , olanzapine , quetiapine , and amisulpiride . [ 8 ] Another large , nonr and omized effectiveness study , the Schizophrenia Outpatient Health Outcomes ( SOHO ) study , also found clozapine to be superior on clinician and patient ratings at six months compared to other antipsychotics . [ 9 ] Based on clinical trials , meta-analyses , and large naturalistic studies clozapine is recommended as the most effective agent in schizophrenia , but the recommendations indicate that it should only be used when other agents fail . [ 5 BACKGROUND Approximately 50 % of patients with schizophrenia or schizoaffective disorder attempt suicide , and approximately 10 % die of suicide . Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients . METHODS A multicenter , r and omized , international , 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder , 26.8 % of whom were refractory to previous treatment , who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation . To equalize clinical contact across treatments , all patients were seen weekly for 6 months and then biweekly for 18 months . Subsequent to r and omization , unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts . Suicidal behavior was assessed at each visit . Primary end points included suicide attempts ( including those that led to death ) , hospitalizations to prevent suicide , and a rating of " much worsening of suicidality " from baseline . Masked raters , including an independent suicide monitoring board , determined when end point criteria were achieved . RESULTS Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine ( hazard ratio , 0.76 ; 95 % confidence interval , 0.58 - 0.97 ; P = .03 ) . Fewer clozapine-treated patients attempted suicide ( 34 vs 55 ; P = .03 ) , required hospitalizations ( 82 vs 107 ; P = .05 ) or rescue interventions ( 118 vs 155 ; P = .01 ) to prevent suicide , or required concomitant treatment with antidepressants ( 221 vs 258 ; P = .01 ) or anxiolytics or soporifics ( 301 vs 331 ; P = .03 ) . Overall , few of these high-risk patients died of suicide during the study ( 5 clozapine vs 3 olanzapine-treated patients ; P = .73 ) . CONCLUSIONS Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide . Use of clozapine in this population should lead to a significant reduction in suicidal behavior 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- 
    Output:
    
Cost savings were most sensitive to the proportion of treatment-resistant patients who received clozapine , decrease in inpatient days , cost of inpatient stays , clozapine response rate , and number of patients with treatment-resistant schizophrenia .
Increased  clozapine utilization would result in net cost savings for the VHA