human
***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 Clozapine is associated with significant weight gain and metabolic disturbances .  This multicentre , r and omized study comprised a double-blind , placebo-controlled treatment phase of 16 wk , and an open-label extension phase of 12 wk . Out patients who met DSM-IV-TR criteria for schizophrenia , who were not optimally controlled while on stable dosage of clozapine for > or =3 months and had experienced weight gain of > or = 2.5 kg while taking clozapine , were r and omized ( n=207 ) to aripiprazole at 5 -  15  mg/d or placebo , in addition to a stable dose of clozapine . The primary endpoint was mean change from baseline in body weight at week 16 ( last observation carried forward ) . Secondary endpoints included clinical efficacy , body mass index ( BMI ) and waist circumference . A statistically significant difference in weight loss was reported for aripiprazole vs. placebo ( -2.53 kg vs. -0.38 kg , respectively , difference=-2.15 kg , p<0.001 ) . Aripiprazole-treated patients also showed BMI ( median reduction 0.8 kg/m(2 ) ) and waist circumference reduction ( median reduction 2.0 cm ) vs. placebo ( no change in either parameter , p<0.001 and p=0.001 , respectively ) . Aripiprazole-treated patients had significantly greater reductions in total and low-density lipoprotein ( LDL ) cholesterol . There were no significant differences in Positive and Negative Syndrome Scale total score changes between groups but Clinical Global Impression Improvement and Investigator 's Assessment Question naire scores favoured aripiprazole over placebo .  Safety and tolerability were generally comparable between groups . Combining aripiprazole and clozapine result ed in significant weight , BMI and fasting cholesterol benefits to patients suboptimally treated with clozapine . Improvements may reduce metabolic risk factors associated with clozapine treatment 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 The treatment of schizophrenia with multiple antipsychotic drugs is common , but the benefits and risks are not known . METHODS In a r and omized , double-blind study , we evaluated patients with schizophrenia and a poor response to treatment with clozapine .  The patients continued to take clozapine and were r and omly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo . This course of treatment was followed by an optional 18 weeks of augmentation with risperidone . The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale ( PANSS ) . The secondary outcomes included cognitive functioning . RESULTS A total of 68 patients were r and omly assigned to treatment . In the double-blind phase , the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups . There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo : 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment ( P=0.38 ) . The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 ( 95 percent confidence interval , -7.3 to 7.0 ) . The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group ( P=0.02 for the comparison between the two groups in the change from baseline ) . The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group ( 16.2 vs. 1.8 mg per deciliter [ 0.90 vs. 0.10 mmol per liter ] , P=0.04 ) . The incidence and severity of other side effects did not differ between the two groups . CONCLUSIONS In this short-term study , the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia . ( Clinical Trials.gov number , NCT00272584 ) BACKGROUND We hypothesised that a combined regimen of clozapine , a relatively weak D2-dopaminergic antagonist , and sulpiride , a selective D2 blocker , would demonstrate a greater antipsychotic efficacy by enhancing the D2 blockade of clozapine . METHOD Twenty-eight people with schizophrenia , previously unresponsive to typical antipsychotics and only partially responsive to current treatment with clozapine  , received , double-blind , 600 mg/day sulpiride or placebo , in addition to an ongoing clozapine treatment . The clinical status was evaluated before , during , and at the end of 10 weeks of sulpiride addition using the Brief Psychiatric Rating Scale ( BPRS ) , Scale for the Assessment of Positive Symptoms ( SAPS ) , Scale for the Assessment of Negative Symptoms , and Hamilton Rating Scale for Depression . RESULTS The clozapine-sulpiride group exhibited substantially greater and significant improvements in positive and negative psychotic symptoms . About half of them , characterised by a younger age and lower baseline SAPS scores , had a mean reduction of 42.4 and 50.4 % in their BPRS and SAPS scores , respectively . CONCLUSIONS A subgroup of patients with chronic schizophrenia may substantially benefit from sulpiride addition to clozapine 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 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 
    Output:
    
agent
At the time of this review , seven AAPs were available in Canada : aripiprazole clozapine olanzapine paliperidone quetiapine risperidone ziprasidone
***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 Clozapine is associated with significant weight gain and metabolic disturbances .  This multicentre , r and omized study comprised a double-blind , placebo-controlled treatment phase of 16 wk , and an open-label extension phase of 12 wk . Out patients who met DSM-IV-TR criteria for schizophrenia , who were not optimally controlled while on stable dosage of clozapine for > or =3 months and had experienced weight gain of > or = 2.5 kg while taking clozapine , were r and omized ( n=207 ) to aripiprazole at 5 -  15  mg/d or placebo , in addition to a stable dose of clozapine . The primary endpoint was mean change from baseline in body weight at week 16 ( last observation carried forward ) . Secondary endpoints included clinical efficacy , body mass index ( BMI ) and waist circumference . A statistically significant difference in weight loss was reported for aripiprazole vs. placebo ( -2.53 kg vs. -0.38 kg , respectively , difference=-2.15 kg , p<0.001 ) . Aripiprazole-treated patients also showed BMI ( median reduction 0.8 kg/m(2 ) ) and waist circumference reduction ( median reduction 2.0 cm ) vs. placebo ( no change in either parameter , p<0.001 and p=0.001 , respectively ) . Aripiprazole-treated patients had significantly greater reductions in total and low-density lipoprotein ( LDL ) cholesterol . There were no significant differences in Positive and Negative Syndrome Scale total score changes between groups but Clinical Global Impression Improvement and Investigator 's Assessment Question naire scores favoured aripiprazole over placebo .  Safety and tolerability were generally comparable between groups . Combining aripiprazole and clozapine result ed in significant weight , BMI and fasting cholesterol benefits to patients suboptimally treated with clozapine . Improvements may reduce metabolic risk factors associated with clozapine treatment 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 The treatment of schizophrenia with multiple antipsychotic drugs is common , but the benefits and risks are not known . METHODS In a r and omized , double-blind study , we evaluated patients with schizophrenia and a poor response to treatment with clozapine .  The patients continued to take clozapine and were r and omly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo . This course of treatment was followed by an optional 18 weeks of augmentation with risperidone . The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale ( PANSS ) . The secondary outcomes included cognitive functioning . RESULTS A total of 68 patients were r and omly assigned to treatment . In the double-blind phase , the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups . There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo : 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment ( P=0.38 ) . The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 ( 95 percent confidence interval , -7.3 to 7.0 ) . The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group ( P=0.02 for the comparison between the two groups in the change from baseline ) . The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group ( 16.2 vs. 1.8 mg per deciliter [ 0.90 vs. 0.10 mmol per liter ] , P=0.04 ) . The incidence and severity of other side effects did not differ between the two groups . CONCLUSIONS In this short-term study , the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia . ( Clinical Trials.gov number , NCT00272584 ) BACKGROUND We hypothesised that a combined regimen of clozapine , a relatively weak D2-dopaminergic antagonist , and sulpiride , a selective D2 blocker , would demonstrate a greater antipsychotic efficacy by enhancing the D2 blockade of clozapine . METHOD Twenty-eight people with schizophrenia , previously unresponsive to typical antipsychotics and only partially responsive to current treatment with clozapine  , received , double-blind , 600 mg/day sulpiride or placebo , in addition to an ongoing clozapine treatment . The clinical status was evaluated before , during , and at the end of 10 weeks of sulpiride addition using the Brief Psychiatric Rating Scale ( BPRS ) , Scale for the Assessment of Positive Symptoms ( SAPS ) , Scale for the Assessment of Negative Symptoms , and Hamilton Rating Scale for Depression . RESULTS The clozapine-sulpiride group exhibited substantially greater and significant improvements in positive and negative psychotic symptoms . About half of them , characterised by a younger age and lower baseline SAPS scores , had a mean reduction of 42.4 and 50.4 % in their BPRS and SAPS scores , respectively . CONCLUSIONS A subgroup of patients with chronic schizophrenia may substantially benefit from sulpiride addition to clozapine 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 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 
    Output:
    