as a strategy for antipsychotic treatment of schizophrenia , monotherapy is clearly optimal when both effective and tolerated . when a patient fails to respond to an adequate dose of an antipsychotic , however , the alternatives include switching , administering a dose higher than the licensed dose , polypharmacy or clozapine . clozapine is the only option with established efficacy , but is less manageable than other antipsychotics , with a relatively high frequency of clozapine - induced agranulocytosis . little evidence has been accumulated from acute - phase practice , as enrolling acute psychotic and agitated patients in randomized clinical trials is challenging , particularly when using a double - blind design . however , most clinical guidelines are based on findings from double - blind trials , which include ideal patients.1 ) such guidelines are therefore not necessarily useful in actual clinical practice . from this practical perspective , strategies for early non - response to an antipsychotic drug in acute - phase schizophrenia are discussed ( fig . how long an antipsychotic should be trialed before being viewed as ineffective is a key unanswered question in clinical trials for patients with schizophrenia.2 ) although previous studies have identified early non - response as a robust predictor of subsequent non - response with continued treatment of the same medication,3,4,5,6,7 ) those studies were retrospective in nature . the first prospective study was performed by kinon et al.8 ) finding early response / non - response to risperidone at 2 weeks as a reliable clinical marker of subsequent clinical outcomes ( table 1 ) . we examined whether early response / non - response to risperidone according to the clinical global impressions - improvement scale ( cgi - i ) at 2 weeks could predict subsequent response in the treatment of acute - phase schizophrenia.9 ) at 4 weeks , 81% of risperidone early responders achieved 50% response , whereas only 9% of early non - responders staying on risperidone achieved 50% response , with a negative likelihood ratio of 0.057 . in contrast , the negative likelihood ratio for the prediction of 50% response at 4 weeks based on early response status to olanzapine at 2 weeks was 0.28 , suggesting this prediction was not necessarily applicable to olanzapine . levine and leucht10 ) recently reanalyzed data from a double - blind , randomized , multicenter , international clinical trial comparing the effectiveness of treatment with olanzapine and haloperidol in recent - onset psychotic patients , in which patients were followed up to 84 weeks.11 ) they reported that early response ( i.e. , within 2 weeks ) is marked by up to 39 weeks of longer subsequent symptom response than non - response ( i.e. , in the initial 4 weeks ) , and infrequently differs to delayed - response ( i.e. , 3 - 4 weeks ) . as half of patients were allocated to receive olanzapine , results from the reanalysis may not necessarily be applicable to risperidone . furthermore , participants were defined as patients with recent - onset psychosis with an interval since first onset of psychotic symptoms of 1 month but 60 months prior to study entry , indicating that patients were not necessarily in the acute phase . mean total scores for the positive and negative syndrome scale ( panss ) at baseline were relatively low , i.e. : early - responder , 57.24 ; delayed - responder , 61.93 ; and non - responder , 78.32 , also indicating that most cases were not in the acute phase . derks et al.12 ) reported data from 299 first - episode patients who completed the full 12-month european first - episode schizophrenia trial , finding that remission status was correctly predicted in 61% of patients based on baseline and 2-week assessments , and this percentage increased to 63% and 68% , respectively , with the inclusion of 4- and 6-week assessments , respectively . accordingly , they concluded that earlier 2-week measures of response are associated with remission , and that as the increase in prediction accuracy by including 4- and 6-week assessments is modest , whether such improvement is clinically relevant remains uncertain . focusing on acutely psychotic patients , o'gorman et al.13 ) reported that from two separate pooled analyses of two placebo - controlled and two active comparator ( risperidone and olanzapine ) randomized trials of ziprasidone in schizophrenia , non - improvement in weeks 1 or 2 was highly predictive of non - response , and week 2 improvement was more reliably predictive of subsequent outcome than week 1 improvement , with high sensitivity and specificity . giegling et al.14 ) reported that a panss reduction 16% at 1 week predicts non - response at 3 weeks of treatment with haloperidol ( specificity 92% , sensitivity 82% ) , and , conversely , a panss reduction 23% at 1 week of treatment predicts response at 3 weeks , with 84% specificity and 86% sensitivity . considering our results that non - response to risperidone at 2 weeks can predict subsequent response in newly admitted patients with acute schizophrenia , and that significant response to olanzapine does not seem to occur until 4 weeks,9 ) the duration for which an antipsychotic should be trialed before being viewed as ineffective might depend on the kind of antipsychotic , such as affinity and specificity for dopamine d2 receptors . according to these findings , an antipsychotic may be able to be viewed as ineffective within 1 - 4 weeks in acute - phase practice , although some differences may exist among specific antipsychotics . before we presume that identifying early non - responders minimizes prolonged exposure to suboptimal or ineffective treatment strategies , alternative treatment strategies such as " switching " , " augmentation " , and " high - dose " antipsychotics should be evaluated . first , we reviewed whether patients who are early non - responders to an antipsychotic and are then switched to another antipsychotic would show significantly greater improvement in psychopathology , compared with those staying on the initial antipsychotic . in a switching study of first - episode patients with schizophrenia who showed residual symptoms following treatment with risperidone , takahashi et al.15 ) reported the rate of responders to olanzapine was 29.3% . they also reported that in another switching study of first - episode patients with schizophrenia who experienced residual symptoms following treatment with olanzapine , the rate of response to risperidone was 35.3%.16 ) however , the patients enrolled were those who were able to complete 12 weeks of treatment with the initial antipsychotic , indicating that they were not in the acute phase . furthermore , those studies lacked a control group of patients staying on the initial antipsychotic , and we therefore can not conclude that switching is indeed a beneficial option . although essock et al.17 ) and rosenheck et al.18 ) reported no benefit of switching antipsychotic medications in analyses of the clinical antipsychotic trials of intervention effectiveness ( catie ) trial , which included a control group , those analyses were post hoc exploratory nature . the first randomized , double - blind study of whether ' switching ' early non - responders to another antipsychotic represents a better strategy than ' staying ' was reported by kinon et al.8 ) they showed that switching to risperidone in early non - responders to olanzapine at week 2 resulted in a small but significantly greater reduction in panss total score and in depressive symptoms . the significant difference in panss total score at end point mean change at week 12 was reportedly 3.49 . we failed to show any robust advantage of the switching strategy for early non - responders within the ordinary doses of risperidone or olanzapine in acute - phase clinical practice , probably due to the lack of statistical power for the randomized phase of the study.9 ) agid et al.19 ) reported that from data gathered from a treatment algorithm implemented in patients with first - episode schizophrenia that employs two antipsychotic trials at increasing doses before clozapine , the percentage response for subjects who switched from olanzapine to risperidone was 4.0% , compared to 25.7% for those who switched from risperidone to olanzapine . thus , whether a switching strategy is effective might depend on the initial antipsychotic administered and the antipsychotic switched to . a substantial proportion of schizophrenia patients receive more than one antipsychotic.20,21,22 ) the current problem is that the degree of polypharmacy being practiced seems far in excess of the supporting data.2 ) in a systematic review of 19 randomized studies , the pooled odds ratio suggested a small effect favoring combination treatment , and positive effects appear to have been associated with studies using clozapine combinations.23 ) however , clozapine is not tolerated by some patients . studies combining non - clozapine second - generation antipsychotics with each other and with the first - generation antipsychotics utilized most in clinical practice are thus required.23 ) kotler et al.24 ) indicated no significant differences in changes to positive or negative symptomatology between patients receiving a combined regimen of olanzapine with sulpiride augmentation and those receiving olanzapine monotherapy among chronic schizophrenia patients unresponsive to olanzapine . kane et al.25 ) reported that addition of aripiprazole to either risperidone or quetiapine in 323 patients showed no greater efficacy than placebo added to either risperidone or quetiapine . in contrast , essock et al.26 ) reported that patients assigned to a switch to monotherapy displayed shorter times to all - cause treatment discontinuation than those assigned to remain on polypharmacy . these studies were indicators of what could happen with antipsychotic combinations in chronic - phase patients . we have presented the first randomized clinical trial of olanzapine augmentation of risperidone in patients non - responsive to risperidone monotherapy in the acute phase.27 ) in the study , early response was defined as cgi - i 3 following 2 weeks of treatment , and early non - responders were then allocated to receive either augmentation with olanzapine ( ris+olz group ) or increased risperidone dose ( ris+ris group ) . although time to treatment discontinuation for any cause was significantly shorter in the ris+ris group than in early responders to risperidone , no significant difference was evident between the ris+olz group and early responders to risperidone . these outcomes justify the inclusion of augmentation arms in additional , larger studies comparing strategies for early non - responders in the treatment of acute - phase schizophrenia . in clinical practice , nearly 50% of olanzapine prescriptions in the united states was reportedly above 20 mg / day28 ) and the median recommended dose for olanzapine by u.s . experts was 30 mg / day.29 ) the upper limit of olanzapine dose in the catie study , in which olanzapine was the most effective in terms of rates of discontinuation , was designed to be 30 mg / day.30 ) in chronic schizophrenia inpatients showing suboptimal response to treatment , one randomized controlled trial allowed the use of high doses of olanzapine.31 ) in that study , clozapine and olanzapine were superior to haloperidol , but no obvious superiority of risperidone over haloperidol was seen . in patients with treatment - resistant schizophrenia , olanzapine at higher - than - customary doses reportedly demonstrated similar efficacy to clozapine32 ) or was less effective than clozapine.33 ) for acute - phase patients , we presented the first randomized clinical trial that examined whether olanzapine at 40 mg / day would be superior to risperidone at 12 mg / day.34 ) as the numbers of patients allocated to each treatment group did not reach the required numbers set by power analysis , the results were not conclusive . although time to treatment discontinuation due to any cause did not differ between treatment groups , more than half of cases that were non - responsive to conventional doses showed moderate improvement on subsequent treatment with high doses . in the study , serum olanzapine concentrations at the time of oral 20 mg / day could be obtained from 5 out of 7 patients who subsequently required high - dose olanzapine . all values were > 30 ng / ml , which were appropriate with regard to a therapeutic range of 20 - 50 ng / ml . the reason for requiring high - dose olanzapine in the treatment of acute - phase schizophrenia thus can not be explained simply based on pharmacokinetics . furthermore , 2 of 5 patients who subsequently required high - dose olanzapine , and from whom serum olanzapine concentrations could be obtained , were antipsychotic - nave , suggesting that the etiology of dopamine supersensitivity psychosis was not applicable in those cases.35 ) how long an antipsychotic should be trialed before being viewed as ineffective is a key unanswered question in clinical trials for patients with schizophrenia.2 ) although previous studies have identified early non - response as a robust predictor of subsequent non - response with continued treatment of the same medication,3,4,5,6,7 ) those studies were retrospective in nature . the first prospective study was performed by kinon et al.8 ) finding early response / non - response to risperidone at 2 weeks as a reliable clinical marker of subsequent clinical outcomes ( table 1 ) . we examined whether early response / non - response to risperidone according to the clinical global impressions - improvement scale ( cgi - i ) at 2 weeks could predict subsequent response in the treatment of acute - phase schizophrenia.9 ) at 4 weeks , 81% of risperidone early responders achieved 50% response , whereas only 9% of early non - responders staying on risperidone achieved 50% response , with a negative likelihood ratio of 0.057 . in contrast , the negative likelihood ratio for the prediction of 50% response at 4 weeks based on early response status to olanzapine at 2 weeks was 0.28 , suggesting this prediction was not necessarily applicable to olanzapine . levine and leucht10 ) recently reanalyzed data from a double - blind , randomized , multicenter , international clinical trial comparing the effectiveness of treatment with olanzapine and haloperidol in recent - onset psychotic patients , in which patients were followed up to 84 weeks.11 ) they reported that early response ( i.e. , within 2 weeks ) is marked by up to 39 weeks of longer subsequent symptom response than non - response ( i.e. , in the initial 4 weeks ) , and infrequently differs to delayed - response ( i.e. , 3 - 4 weeks ) . as half of patients were allocated to receive olanzapine , results from the reanalysis may not necessarily be applicable to risperidone . furthermore , participants were defined as patients with recent - onset psychosis with an interval since first onset of psychotic symptoms of 1 month but 60 months prior to study entry , indicating that patients were not necessarily in the acute phase . mean total scores for the positive and negative syndrome scale ( panss ) at baseline were relatively low , i.e. : early - responder , 57.24 ; delayed - responder , 61.93 ; and non - responder , 78.32 , also indicating that most cases were not in the acute phase . derks et al.12 ) reported data from 299 first - episode patients who completed the full 12-month european first - episode schizophrenia trial , finding that remission status was correctly predicted in 61% of patients based on baseline and 2-week assessments , and this percentage increased to 63% and 68% , respectively , with the inclusion of 4- and 6-week assessments , respectively . accordingly , they concluded that earlier 2-week measures of response are associated with remission , and that as the increase in prediction accuracy by including 4- and 6-week assessments is modest , whether such improvement is clinically relevant remains uncertain . focusing on acutely psychotic patients , o'gorman et al.13 ) reported that from two separate pooled analyses of two placebo - controlled and two active comparator ( risperidone and olanzapine ) randomized trials of ziprasidone in schizophrenia , non - improvement in weeks 1 or 2 was highly predictive of non - response , and week 2 improvement was more reliably predictive of subsequent outcome than week 1 improvement , with high sensitivity and specificity . giegling et al.14 ) reported that a panss reduction 16% at 1 week predicts non - response at 3 weeks of treatment with haloperidol ( specificity 92% , sensitivity 82% ) , and , conversely , a panss reduction 23% at 1 week of treatment predicts response at 3 weeks , with 84% specificity and 86% sensitivity . considering our results that non - response to risperidone at 2 weeks can predict subsequent response in newly admitted patients with acute schizophrenia , and that significant response to olanzapine does not seem to occur until 4 weeks,9 ) the duration for which an antipsychotic should be trialed before being viewed as ineffective might depend on the kind of antipsychotic , such as affinity and specificity for dopamine d2 receptors . according to these findings , an antipsychotic may be able to be viewed as ineffective within 1 - 4 weeks in acute - phase practice , although some differences may exist among specific antipsychotics . before we presume that identifying early non - responders minimizes prolonged exposure to suboptimal or ineffective treatment strategies , alternative treatment strategies such as " switching " , " augmentation " , and " high - dose " antipsychotics should be evaluated . first , we reviewed whether patients who are early non - responders to an antipsychotic and are then switched to another antipsychotic would show significantly greater improvement in psychopathology , compared with those staying on the initial antipsychotic . in a switching study of first - episode patients with schizophrenia who showed residual symptoms following treatment with risperidone , takahashi et al.15 ) reported the rate of responders to olanzapine was 29.3% . they also reported that in another switching study of first - episode patients with schizophrenia who experienced residual symptoms following treatment with olanzapine , the rate of response to risperidone was 35.3%.16 ) however , the patients enrolled were those who were able to complete 12 weeks of treatment with the initial antipsychotic , indicating that they were not in the acute phase . furthermore , those studies lacked a control group of patients staying on the initial antipsychotic , and we therefore can not conclude that switching is indeed a beneficial option . although essock et al.17 ) and rosenheck et al.18 ) reported no benefit of switching antipsychotic medications in analyses of the clinical antipsychotic trials of intervention effectiveness ( catie ) trial , which included a control group , those analyses were post hoc exploratory nature . the first randomized , double - blind study of whether ' switching ' early non - responders to another antipsychotic represents a better strategy than ' staying ' was reported by kinon et al.8 ) they showed that switching to risperidone in early non - responders to olanzapine at week 2 resulted in a small but significantly greater reduction in panss total score and in depressive symptoms . the significant difference in panss total score at end point mean change at week 12 was reportedly 3.49 . we failed to show any robust advantage of the switching strategy for early non - responders within the ordinary doses of risperidone or olanzapine in acute - phase clinical practice , probably due to the lack of statistical power for the randomized phase of the study.9 ) agid et al.19 ) reported that from data gathered from a treatment algorithm implemented in patients with first - episode schizophrenia that employs two antipsychotic trials at increasing doses before clozapine , the percentage response for subjects who switched from olanzapine to risperidone was 4.0% , compared to 25.7% for those who switched from risperidone to olanzapine . thus , whether a switching strategy is effective might depend on the initial antipsychotic administered and the antipsychotic switched to . a substantial proportion of schizophrenia patients receive more than one antipsychotic.20,21,22 ) the current problem is that the degree of polypharmacy being practiced seems far in excess of the supporting data.2 ) in a systematic review of 19 randomized studies , the pooled odds ratio suggested a small effect favoring combination treatment , and positive effects appear to have been associated with studies using clozapine combinations.23 ) however , clozapine is not tolerated by some patients . studies combining non - clozapine second - generation antipsychotics with each other and with the first - generation antipsychotics utilized most in clinical practice are thus required.23 ) kotler et al.24 ) indicated no significant differences in changes to positive or negative symptomatology between patients receiving a combined regimen of olanzapine with sulpiride augmentation and those receiving olanzapine monotherapy among chronic schizophrenia patients unresponsive to olanzapine . kane et al.25 ) reported that addition of aripiprazole to either risperidone or quetiapine in 323 patients showed no greater efficacy than placebo added to either risperidone or quetiapine . in contrast , essock et al.26 ) reported that patients assigned to a switch to monotherapy displayed shorter times to all - cause treatment discontinuation than those assigned to remain on polypharmacy . these studies were indicators of what could happen with antipsychotic combinations in chronic - phase patients . we have presented the first randomized clinical trial of olanzapine augmentation of risperidone in patients non - responsive to risperidone monotherapy in the acute phase.27 ) in the study , early response was defined as cgi - i 3 following 2 weeks of treatment , and early non - responders were then allocated to receive either augmentation with olanzapine ( ris+olz group ) or increased risperidone dose ( ris+ris group ) . although time to treatment discontinuation for any cause was significantly shorter in the ris+ris group than in early responders to risperidone , no significant difference was evident between the ris+olz group and early responders to risperidone . these outcomes justify the inclusion of augmentation arms in additional , larger studies comparing strategies for early non - responders in the treatment of acute - phase schizophrenia . in clinical practice , nearly 50% of olanzapine prescriptions in the united states was reportedly above 20 mg / day28 ) and the median recommended dose for olanzapine by u.s . experts was 30 mg / day.29 ) the upper limit of olanzapine dose in the catie study , in which olanzapine was the most effective in terms of rates of discontinuation , was designed to be 30 mg / day.30 ) in chronic schizophrenia inpatients showing suboptimal response to treatment , one randomized controlled trial allowed the use of high doses of olanzapine.31 ) in that study , clozapine and olanzapine were superior to haloperidol , but no obvious superiority of risperidone over haloperidol was seen . in patients with treatment - resistant schizophrenia , olanzapine at higher - than - customary doses reportedly demonstrated similar efficacy to clozapine32 ) or was less effective than clozapine.33 ) for acute - phase patients , we presented the first randomized clinical trial that examined whether olanzapine at 40 mg / day would be superior to risperidone at 12 mg / day.34 ) as the numbers of patients allocated to each treatment group did not reach the required numbers set by power analysis , the results were not conclusive . although time to treatment discontinuation due to any cause did not differ between treatment groups , more than half of cases that were non - responsive to conventional doses showed moderate improvement on subsequent treatment with high doses . in the study , serum olanzapine concentrations at the time of oral 20 mg / day could be obtained from 5 out of 7 patients who subsequently required high - dose olanzapine . all values were > 30 ng / ml , which were appropriate with regard to a therapeutic range of 20 - 50 ng / ml . the reason for requiring high - dose olanzapine in the treatment of acute - phase schizophrenia thus can not be explained simply based on pharmacokinetics . furthermore , 2 of 5 patients who subsequently required high - dose olanzapine , and from whom serum olanzapine concentrations could be obtained , were antipsychotic - nave , suggesting that the etiology of dopamine supersensitivity psychosis was not applicable in those cases.35 ) to establish strategies for early non - response to an antipsychotic drug in the treatment of acute - phase schizophrenia , evidence for antipsychotic switching , augmentation , or high - doses has gradually been accumulating . more studies performed in actual clinical practice with minimal bias are required to assist clinicians in making rational treatment decisions .
as a strategy for antipsychotic treatment of schizophrenia , monotherapy is clearly optimal when both effective and tolerated . when a patient fails to respond to an adequate dose of an antipsychotic , alternatives include switching , administering a higher dose ( above the licensed dose ) , polypharmacy or clozapine 
 . 
 clozapine is the only option with established efficacy , but is less manageable than other antipsychotics . 
 we therefore reviewed other options , focusing on the treatment of acute - phase schizophrenia . 
 according to recent evidence , an antipsychotic may be viewed as ineffective within 1 - 4 weeks in acute - phase practice , although some differences may exist among antipsychotics . 
 whether a switching strategy is effective might depend on the initial antipsychotic and which antipsychotic is switched to . 
 as weak evidence points toward augmentation being superior to continuation of the initial antipsychotic , inclusion of augmentation arms in larger studies comparing strategies for early non - responders in the acute - phase is justified . with respect to high - doses , little evidence is available regarding acute - phase treatment , and the issue remains controversial . 
 although evidence for antipsychotic switching , augmentation , and high - doses has gradually been accumulating , more studies performed in real clinical practice with minimal bias are required to establish strategies for early non - response to an antipsychotic drug in the treatment of acute - phase schizophrenia .