***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: OBJECTIVE Despite the frequent use of the Positive and Negative Syndrome Scale ( PANSS ) for rating the symptoms of schizophrenia , the clinical meaning of its total score and of the cut-offs that are used to define treatment response ( e.g. at least 20 % or 50 % reduction of the baseline score ) are as yet unclear . We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions ( CGI ) . METHOD PANSS and CGI ratings at baseline ( n = 4091 ) , and after one , two , four and six weeks of treatment taken from a pooled data base of seven pivotal , multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking . RESULTS Being considered " mildly ill " according to the CGI approximately corresponded to a PANSS total score of 58 , " moderately ill " to a PANSS of 75 , " markedly ill " to a PANSS of 95 and severely ill to a PANSS of 116 . To be " minimally improved " according to the CGI score was associated with a mean percentage PANSS reduction of 19 % , 23 % , 26 % and 28 % at weeks 1 , 2 , 4 and 6 , respectively . The corresponding figures for a CGI rating " much improved " were 40 % , 45 % , 51 % and 53 % . CONCLUSIONS The results provide a better framework for underst and ing the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations . Such studies may ideally use at least a 50 % reduction from baseline cut-off to define response rather than lower thresholds . In treatment resistant population s , however , even a small improvement can be important , so that a 25 % cut-off might be appropriate This study attempts : ( 1 ) to verify that serum antimuscarinic activity is related to clozapine dose , and more importantly to clozapine plasma concentrations ; ( 2 ) to explore whether norclozapine has serum antimuscarinic activity ; ( 3 ) to explore whether antimuscarinic activity is related to clozapine side effects ; and ( 4 ) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics . In 39 patients participating in a double-blind clozapine study , the  [3H]QNB assay was used to measure serum antimuscarinic activity : ( 1 ) on baseline medications ; ( 2 ) after a 4-week haloperidol trial ; ( 3 ) after a 16-week clozapine trial of either 100 , 300 , or 600 mg/d ; and ( 4 ) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders . Clozapine levels predicted serum antimuscarinic activity better than clozapine dose . At the end of the 1st clozapine trial , the correlation with the levels explained 69 % of the variance of serum antimuscarinic activity ( r = 0.83 , P < 0.001 , N = 34 ) .  Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d . After correcting for clozapine levels , the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant ( r = 0.54 , F = 26.7 , df = 1.65 , P < 0.001 ) . Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial . Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians . In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment McEvoy et al. 's study in 1999 , which used cotinine levels but had limited power , suggested that clozapine treatment may be associated with a mild smoking decrease ( particularly when plasma clozapine levels are > 150 ng/ml ) . Some naturalistic studies also suggest that clozapine treatment may be associated with a mild smoking decrease . The present study included 38 schizophrenic daily smokers from a double-blind clozapine trial . Five analyses were tested for significant decreases in plasma cotinine levels from a haloperidol baseline to : ( 1 ) the end of clozapine trials regarding clozapine doses ( 100 , 300 or 600 mg/day ) , ( 2 ) the end of the clozapine trial where the highest plasma clozapine level was achieved , ( 3 ) the end of the clozapine trial where a clozapine level in the 150 - 450 ng/ml range was achieved , ( 4 ) the end of the first clozapine trial regardless of clozapine dose , and ( 5 ) the end of the last clozapine trial in the study . The first and straightforward analysis by dose showed no clozapine effects on smoking . The second and the third analyses ( an attempt to mimic the design by McEvoy et al. [ McEvoy , J.P. , Freudenreich , O. , Wilson , W.H. , 1999 . Smoking and therapeutic response to clozapine in patients with schizophrenia . Biol . Psychiat . 46 , 125 - 129 . ] ) also indicated that there was not a significant effect of clozapine on smoking . The fourth and five analyses were also negative . None of the five analyses in our clozapine trial demonstrated that clozapine had major effects on smoking . This study can not rule out that in some subjects , clozapine treatment may be associated with a small decrease in smoking . New prospect i ve longitudinal studies using repeated cotinine and clozapine levels are needed to explore whether clozapine may reduce smoking in some patients The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more .  ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas BACKGROUND Clozapine is currently restricted to patients who have failed at least two trials of other antipsychotic medications because of concerns that its use as a first-line agent would lead to greater mortality , mainly through agranulocytosis . AIMS OF THE STUDY We sought to determine the cost-effectiveness of allowing clozapine to be a first-line treatment versus the current policy of restricting clozapine to third-line status . METHODS We performed a cost-effectiveness analysis using published data from r and omized controlled trials and epidemiologic studies . The target population was patients with schizophrenia in an acute psychotic episode , with a lifetime time horizon and societal perspective . Outcome measures included life expectancy , quality -adjusted life expectancy , costs , and cost-effectiveness ratios . RESULTS Using clozapine as a first agent would lead to modest gains in life-expectancy as well as quality -adjusted life expectancy , relative to restricting its use to patients who failed 2 conventional antipsychotics . The cost-effectiveness ratio of using clozapine first vs. using clozapine third would be $ 24,100 per quality -adjusted life year ( QALY ) . In 1-way and probabilistic sensitivity analyses , these findings were robust to a variety of assumptions . DISCUSSION Allowing clozapine to be a first-line agent may lead to small gains in life expectancy at moderate but acceptable costs . IMPLICATION S While these results do not shed light on whether clozapine should be the preferred first-line strategy , they do suggest that clozapine should be added to the armamentarium of possible treatments for treatment-sensitive as well as treatment-resistant schizophrenia Preliminary results of a double-blind clozapine study in a population of chronic psychotic patients at a state psychiatric facility are reported . Thirty " treatment-refractory " schizophrenic patients given a diagnosis according to DSM-III-R criteria ( mean age of 44 + /- 9.1 years and a duration of illness of 24.9 + /- 8.8 years ) who received 300 mg or 600 mg of clozapine  and r and omized in a double-blind fashion were analyzed . Subjects were evaluated using the Brief Psychiatric Rating Scale ( BPRS ) and the Clinical Global Impression ( CGI ) Scale on a weekly basis for 16 weeks . Based on the changes in their CGI scores at week 16 of clozapine treatment , subjects were retrospectively categorized as " improvers " ( N = 12 ) and " nonimprovers " ( N = 18 ) . The two groups were compared for changes in total BPRS and BPRS factor scores . In terms of total BPRS scores , we expected a difference between the two groups because they were categorized based on changes in their CGI scores . However , the total BPRS scores in improvers showed a significant decrease by week 6 of clozapine treatment . On analyzing the four BPRS factors , the improvers showed improvement in the thinking disturbance factor by week 1 that remained steady from week 7 . On the hostility-suspiciousness factor , the improvers showed an improvement across time when compared with nonimprovers . The withdrawal-retardation factor showed improvement in both groups across time , whereas the anxiety-depression factor was least influenced by clozapine . These observations suggested that all BPRS symptom factors did not uniformly contribute to improvement in overall psychopathology , which was observed as a decrease in total BPRS scores 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 . DSM-III schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospect i ve , single-blind trial of haloperidol ( mean dosage , 61 + /- 14 mg/d ) for six weeks . Patients whose condition remained unimproved were then r and omly assigned , in a double-blind manner , to clozapine ( up to 900 mg/d ) or chlorpromazine ( up to 1800 mg/d ) for six weeks . Two hundred sixty-eight patients were entered in the double-blind comparison . When a priori criteria were used , 30 % of the clozapine-treated patients were categorized as responders compared with 4 % of chlorpromazine-treated patients . Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale , Clinical Global Impression Scale , and Nurses ' Observation Scale for Inpatient Evaluation ; this improvement included " negative " as well as positive symptom areas . Although no cases of agranulocytosis occurred during this relatively brief study , in our view , the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients Steady-state blood clozapine concentrations in 58 schizophrenic patients varied more than 45-fold ( 40 - 1911 ng/mL ) after fixed-dose treatment ( 400 mg/day ) . Discriminant function analysis determined that a blood clozapine concentration of 420 ng/mL optimally distinguished responders from nonresponders . After 4 weeks of treatment , only 8 % of those patients with a blood clozapine concentration < 420 ng/mL responded compared with 60 % of those who had a blood clozapine concentration > 420 ng/mL. When plasma concentrations were increased above 420 ng/mL ( by a double-blind r and om assignment procedure ) , nonresponders increased their response rate to 73 % if their plasma concentrations at Week 12 exceeded 420 ng/mL compared with a response rate of 29 % if their Week 12 levels remained below 420 ng/mL ( chi 2 = 4.2 , p < .04 ) OBJECTIVE This study sought to determine the relationships between serum clozapine  levels and therapeutic response . METHOD Fifty-six in patients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics  were r and omly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges : low ( 50 - 150 
    Output:
    
We found no evidence of effect on mental state between st and ard , low and very low dose regimes , but we did not identify any trials on high or very high doses of clozapine .
There was limited evidence that the incidence of some adverse effects was greater at st and ard dose compared to lower dose regimes .