title: What does the PANSS mean? Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double‐blind comparative study Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial. A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. Clozapine and “High-Dose” Olanzapine in Refractory Early-Onset Schizophrenia: A 12-Week Randomized and Double-Blind Comparison Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. Risperidone in treatment-refractory schizophrenia. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Adverse Effects and Laboratory Parameters of High-Dose Olanzapine vs. Clozapine in Treatment-Resistant Schizophrenia Adjunctive Risperidone for Partially Responsive People with Schizophrenia Treated with Clozapine Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder.
abstract: 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 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 Forty‐four chronic schizophrenic in patients participated in this multicentre 12‐week parallel‐group double‐blind trial . After a run‐in period of 2 weeks and a single‐blind placebo wash‐out of 1 week , they were r and omly assigned to treatment with either the serotonin2 and dopamine‐D2 antagonist risperidone or haloperidol .  Two patients were excluded from the efficacy analysis . Five patients dropped out in the haloperidol group and 1 in the risperidone group . At the end of the trial , the mean daily dose was 12 mg for risperidone and 10 mg for haloperidol . The risperidone group showed greater improvement on the Positive and Negative Syndrome Scale for Schizophrenia , the Schedule for Affective Disorders and Schizophrenia – change version , and the Nurses ’ Observation Scale for Inpatient Evaluation . The improvement of negative symptoms was more pronounced in the risperidone group until week 8 of double‐blind treatment . The consumption of antiparkinsonian medication was 10 times lower with risperidone . Both drugs were well tolerated and the laboratory , endocrinological and cardiovascular safety parameters were comparable . This study suggests that risperidone is comparable to haloperidol as an antipsychotic , but that it has a safer EPS profile INTRODUCTION Only limited data are available on the effectiveness of augmented antipsychotics to clozapine therapy in chronic schizophrenia . We conducted a r and omized , double-blind , placebo-controlled pilot study to evaluate the efficacy and safety of augmentation with the atypical neuroleptic amisulpride to clozapine in a small sample group of patients . METHODS 16 patients with the DSM-IV diagnosis of chronic schizophrenia and partially responsive to clozapine participated in this pilot study . Patients on a steady dose of clozapine r and omly received either clozapine and amisulpride 400 mg/day ( n=7 ) or clozapine and amisulpride 600 mg/day ( n=6 ) or clozapine and placebo for 6 weeks ( n=3 ) . Efficacy measures were BPRS , CGI , GAF and MADRS score . Side effects and prolactin levels were obtained . Primary outcome measure were BPRS score changes . RESULTS The beneficial effect of augmented amisulpride at a daily dose of 600 mg was observed in the mean scores of secondary outcome measures , as assessed by GAF , CGI and MADRS . Measures of primary objectives failed to improve significantly . No reduction in BPRS total score was achieved due to lack of power of the study , whereas the BPRS subscore " activity " had a tendency to improve . Amisulpride was more beneficial in a higher than a lower dose . No severe side-effects occurred , but tremor , bradykinesia , akathisia and elevated prolactin levels were recorded . DISCUSSION Augmented amisulpride improved the global outcome of patients suffering from chronic schizophrenia in this pilot study and tended to be a helpful treatment option in cases of partial or non-responsiveness to clozapine . Limitations emerge from the small sample size and lack of power . Further investigation requires a larger number of patients to be included BACKGROUND Clozapine , despite its side-effect burden , has been considered to be the drug of choice for patients with schizophrenia whose psychotic symptoms fail to respond adequately to other anti-psychotic drugs . There are conflicting data concerning the potential utility of olanzapine in treatment-resistant schizophrenia at doses beyond the 10- to 20-mg/day range that has proven to be effective for most nonrefractory patients with schizophrenia . OBJECTIVE The main objective of this study was to compare the efficacy and tolerability of high-dose olanzapine ( target dose , 25 - 45 mg/day ) and clozapine ( 300 - 900 mg/day ) in patients with schizophrenia or schizoaffective disorder who had failed to respond adequately to prior treatment with other antipsychotic drugs . STUDY DESIGN / METHOD This 6-month , r and omized , double-blind , parallel-group study compared the efficacy and tolerability of olanzapine ( mean dose , 34 mg/day ; N = 19 ) or clozapine ( mean dose , 564 mg/day ; N = 21 ) in patients with treatment-resistant schizophrenia or schizoaffective disorder , diagnosed according to DSM-IV criteria . Outcome measures included psychopathology , cognitive performance ( as assessed with a comprehensive neuropsychological test battery ) , and tolerability . The study was conducted between May 2000 and December 2003 . RESULTS Robust and significant ( mostly p < .001 ) improvement in multiple measures of psychopathology , mainly between 6 weeks and 6 months of treatment , was found in both treatment groups , with no significant difference between the 2 treatments except for the Global Assessment of Functioning score , which favored clozapine ( p = .01 ) . Improvement in some domains of cognition was significant- and equivalent for both drugs , as well . Nonsignificantly different improvement in Verbal List Learning-Immediate Recall ( p < .05 ) , Controlled Word Association Test ( p < .05 ) , and Digit Symbol Substitution Test ( p < .001 ) was found . There were no significant differences in extrapyramidal symptoms . Weight gain was significantly ( p = .01 ) greater with olanzapine . CONCLUSIONS Olanzapine , at higher than customary doses , demonstrated similar efficacy to clozapine in treatment-resistant schizophrenia and schizoaffective disorder in this study . However , the small sample size precludes definitively concluding that the 2 treatments are equivalent , at these doses , in treatment-resistant schizophrenia . The metabolic side effects of olanzapine are a limitation in its use . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier NCT00179231 OBJECTIVE The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia .  METHOD In a r and omized , double-blind , placebo-controlled 12-week trial , 40 patients unresponsive or partially responsive to clozapine monotherapy  received a steady dose of clozapine combined with either placebo ( N=20 ) or up to 6 mg/day of risperidone ( N=20 ) . Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale ( BPRS ) and the Scale for the Assessment of Negative Symptoms ( SANS ) , among other measures . Movement disorders were assessed with the Simpson-Angus Rating Scale . RESULTS From baseline to week 6 and week 12 , mean BPRS total and positive symptom subscale scores were reduced significantly in both groups , but the reductions were significantly greater with clozapine/risperidone treatment . Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine/placebo . The adverse event profile for clozapine/risperidone treatment was similar to that for clozapine/placebo .  Simpson-Angus Rating Scale scores were lower with clozapine/risperidone treatment throughout the trial but increased to approach those of clozapine/placebo treatment at week 12 . Clozapine/risperidone treatment did not induce additional weight gain , agranulocytosis , or seizures compared with clozapine/placebo treatment . CONCLUSIONS In patients with a suboptimal response to clozapine , the addition of risperidone improved overall symptoms and positive and negative symptoms of schizophrenia . The combination appears to be safe and well tolerated . Augmentation of clozapine with risperidone may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone OBJECTIVE Combining antipsychotics is common practice in the treatment of schizophrenia . This study investigated aripiprazole adjunctive to risperidone or quetiapine for treating schizophrenia and schizoaffective disorder . METHOD In this multicenter , double-blind , 16-week , placebo-controlled study conducted at 43 American sites from July 2006 to October 2007 , patients with chronic , stable schizophrenia or schizoaffective disorder diagnosed with DSM-IV-TR were r and omly assigned to receive aripiprazole ( 2 - 15 mg/d ) or placebo in addition to a stable regimen of quetiapine ( 400 - 800 mg/d ) or risperidone ( 4 - 8 mg/d ) . The primary outcome measure was the mean change from baseline to endpoint ( week 16 , last observation carried forward ) in the Positive and Negative Syndrome Scale ( PANSS ) total score . RESULTS 323 subjects being treated with either risperidone ( n = 177 ) or quetiapine ( n = 146 ) were r and omly assigned to receive adjunctive aripiprazole ( n = 168 ) or placebo ( n = 155 ) . Baseline characteristics were similar ( mean PANSS total score : aripiprazole , 74.5 ; placebo , 75.9 ) except for history of suicide attempts ( aripiprazole , 27 % ; placebo , 40 % ) . Nearly 70 % of subjects in each arm completed the trial . Adjunctive aripiprazole and placebo groups were similar in the mean change from baseline to endpoint in the PANSS total score ( aripiprazole , -8.8 ; placebo , -8.9 ; P = .942 ) . The incidence of treatment-emergent adverse events was similar between groups . Mean changes in Simpson-Angus Scale , Abnormal Involuntary Movement Scale , and Barnes Akathisia Rating Scale scores were not statistically significantly different . Adjunctive aripiprazole was associated with statistically significantly greater decreases in mean serum prolactin levels from baseline than was adjunctive placebo ( -12.6 ng/mL for aripiprazole vs -2.2 ng/mL for placebo ; P < .001 ) , an effect that was seen in the risperidone subgroup ( -18.7 ng/mL vs -1.9 ng/mL ; P < .001 ) but not in the quetiapine subgroup ( -3.01 ng/mL vs + 0.15 ng/mL ; P = .104 ) . CONCLUSIONS The addition of aripiprazole to risperidone or quetiapine was not associated with improvement in psychiatric symptoms but was generally safe and well tolerated . Further research is warranted to explore whether antipsychotic combination therapy offers benefits to particular patient population s-for example , in cases of hyperprolactinemia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00325689 BACKGROUND The present study evaluated the effectiveness and safety of clozapine versus " high-dose " olanzapine in treatment-refractory adolescents with schizophrenia . METHODS Children , ages 10 - 18 years , who met DSM-IV criteria for schizophrenia and who were resistant or intolerant to at least two antipsychotic drugs were r and omized to receive 12 weeks of double-blind flexibly dosed treatment with clozapine ( n = 18 ) or " high-dose " olanzapine ( up to 30 mg/day ) ( n = 21 ) . The primary efficacy measure was response ( improvement ) , defined as a decrease of 30 % or more in total Brief Psychiatric Rating Scale score from baseline and a Clinical Global Impression Scale improvement rating of " 1 " ( very much improved ) or " 2 " ( much improved ) . RESULTS Significantly more clozapine-treated adolescents met response criteria ( 66 % ) compared with olanzapine-treated subjects ( 33 % ) . Clozapine was superior to olanzapine in terms of reduction of the psychosis cluster scores and negative symptoms from baseline to end point . However , both treatments were associated with significant weight-gain and related metabolic abnormalities . CONCLUSIONS This double-blind r and omized comparison of two second-generation antipsychotic drugs for treatment-refractory adolescents with schizophrenia supports clozapine as the agent of choice . The development of interventions to limit weight gain and metabolic side effects are needed to enhance the risk-benefit profile for both study treatments Aripiprazole is a novel atypical antipsychotic for the treatment of schizophrenia . It is a D2 receptor partial agonist with partial agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2A receptors . The long-term efficacy and safety of aripiprazole ( 30 mg/d ) relative to haloperidol ( 10 mg/d ) were investigated in two 52-wk , r and omized , double-blind , multicentre studies ( using similar protocol s which were prospect ively identified to be pooled for analysis ) in 1294 patients in acute relapse with a diagnosis of chronic schizophrenia and who had previously responded to antipsychotic medications .  Aripiprazole demonstrated long-term efficacy that was comparable or superior to haloperidol across all symptoms measures , including significantly greater improvements for PANSS negative subscale scores and MADRS total score ( p<0.05 ) . The time to discontinuation for any reason was significantly greater with aripiprazole than with haloperidol ( p=0.0001 ) . Time to discontinuation due to adverse events or lack of efficacy was significantly greater with aripiprazole than with haloperidol ( p=0.0001 ) . Aripiprazole was associated with significantly lower scores on all extrapyramidal symptoms assessment s than haloperidol ( p<0.001 ) . In summary , aripiprazole demonstrated efficacy equivalent or superior to haloperidol with associated benefits for safety and tolerability .  Aripiprazole represents a promising new option for the long-term treatment of schizophrenia OBJECTIVE This study compared the specific antiaggressive effects of clozapine with those of olanzapine , risperidone , and haloperidol . METHODS A total of 157 in patients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were r and omly assigned to receive clozapine , olanzapine , risperidone , or haloperidol in a double-blind 14-week trial . The trial was divided into two periods : eight weeks during which the dosage was escalated and then fixed , and six weeks during which variable dosages were used . The hostility item of the Positive and Negative Syndrome Scale ( PANSS ) was the principal outcome measure . Covariates included the items that reflect positive symptoms of schizophrenia ( delusions , suspiciousness or feelings of persecution , gr and iosity , unusual thought content , conceptual disorganization , and hallucinations ) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation ( NOSIE ) . RESULTS Patients differed in their treatment response as measured by the hostility item of the PANSS . The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone . The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking , a formal thought disorder , or hallucinations and independent of sedation as measured by the NOSIE . Neither risperidone nor olanzapine showed superiority to haloperidol . CONCLUSION Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent OBJECTIVE The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies . The authors ' goal was to assess the effects of clozapine , olanzapine , risperidone , and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a r and omized double-blind 14-week trial . METHOD One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were in patients at four hospitals were originally included in the study . The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period . Planned assessment s included fasting glucose and cholesterol , which were collected at baseline and at the end of the 8-week period and the following 6-week period . RESULTS One hundred eight of the 157 patients provided blood sample s at baseline and at least at one point after r and om assignment to clozapine , olanzapine , risperidone , or haloperidol during the treatment trial . Seven of these patients had diabetes ; their glucose levels were > 125 mg/dl at baseline . Data from 101 patients were used for statistical analyses . During the initial 8-week period there was an overall significant increase in mean glucose levels . There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine ( N=27 ) and those given haloperidol ( N=25 ) . The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period ( N=22 ) . Fourteen of the 101 patients developed abnormal glucose levels ( > 125 mg/dl ) during the trial ( six with clozapine , four with olanzapine , three with risperidone , and one with haloperidol ) . Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine ( N=27 ) and those given olanzapine ( N=26 ) ; cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine ( N=22 ) . CONCLUSIONS In this prospect i ve r and omized trial , clozapine , olanzapine , and haloperidol were associated with an increase of plasma glucose level , and clozapine and olanzapine were associated with an increase in cholesterol levels . The mean changes in glucose and cholesterol levels remained within clinical ly normal ranges , but approximately 14 % of the patients developed abnormally high glucose levels during the course of their participation in the study BACKGROUND Prolactin levels are elevated to varying degrees by antipsychotics . Prolactin elevations may result in sexual and other adverse effects , and they may be related to antipsychotic effects . We used the data collected in a trial of antipsychotics to study the differential effect of these drugs on prolactin level , to explore the relation between clinical effects and prolactin level , and to determine the relationship between plasma levels of antipsychotics and prolactin level . METHOD Treatment-resistant patients ( 133 men , 24 women ) diagnosed with DSM-IV schizophrenia or schizoaffective disorder participated in a double-blind , r and omized , 14-week trial comparing clozapine ( N = 40 ) , olanzapine ( N = 39 ) , risperidone ( N = 41 ) , and haloperidol ( N = 37 ) . Plasma levels of prolactin and antipsychotics were determined at baseline and at weeks 5 , 8 , 10 , 12 , and 14 during the trial . Clinical effects were measured with the Positive and Negative Syndrome Scale and the Extrapyramidal Symptom Rating Scale . Statistical analyses were limited to the 75 men for whom repeated prolactin levels were available . Data were gathered from June 1996 to December 1999 . RESULTS Risperidone caused significant elevation of prolactin levels ( p < .05 ) that appeared to be dose-dependent . Clozapine and olanzapine were associated with decreases of prolactin , whereas haloperidol led to a minor , nonsignificant increase . Plasma olanzapine and prolactin levels were correlated . Prolactin levels were not related to clinical improvement or extrapyramidal side effects . CONCLUSION Antipsychotics show major differences in their effects on prolactin , and risperidone has clearly the most robust effect OBJECTIVE The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia . METHOD Sixty-seven medication-unresponsive subjects were r and omly assigned to treatment with risperidone ( N = 34 ) or haloperidol ( N = 33 ) . After a 3 - 7 day-placebo washout period , there was a 4-week , double-blind , fixed-dose comparison trial that was followed by a 4-week , flexible-dose phase . Measures of clinical change were quantified by st and ard psychopathologic and neuromotor instruments . RESULTS Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale ( BPRS ) after the first 4 weeks of treatment . Risperidone did not show any advantage over haloperidol after an additional 4 weeks . Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group ( 24 % ) than for the haloperidol group ( 11 % ) . Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks ( 20 % versus 63 % ) ; they also had significantly les observable akathisia ( 24 % versus 53 % ) and significantly less severe tardive dyskinesia . Baseline characteristics that correlated significantly with risperidone response were positive symptoms , conceptual disorganization , akathisia , and tardive dyskinesia . CONCLUSIONS Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia . Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone OBJECTIVE The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients . METHOD In a controlled double-blind , multicenter study , 86 in patients with chronic schizophrenia ( DSM-III-R ) , who were resistant to or intolerant of conventional neuroleptics , were r and omly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period . After a 1-week dose-titration phase , doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient 's response . The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine . Treatment efficacy and safety were evaluated with several well-known rating scales . RESULTS Both risperidone and clozapine significantly reduced the severity of psychotic symptoms ( scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale ) from baseline , with no significant between-group differences . At endpoint , 67 % of the risperidone group and 65 % of the clozapine group were clinical ly improved ( reduction of 20 % or more in total Positive and Negative Syndrome Scale score ) . Risperidone appeared to have a faster onset of action . In both groups extrapyramidal symptoms and other adverse events were few , and their severity was generally mild . Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness . CONCLUSIONS Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics Patients with treatment-resistant schizophrenia pose a major challenge to caregivers since only clozapine is documented as having superior efficacy in this population . Although olanzapine is similar to clozapine in structure and receptor profile , it has not been proven to have superior efficacy for this patient group . Nonetheless , olanzapine is being increasingly used in higher doses as clinicians attempt to find a more effective and tolerable therapy for refractory patients . Furthermore , there are little data comparing olanzapine and clozapine in this population . Thirteen patients participated in a r and omized double-blind 16-week crossover study of  clozapine therapy ( 450 mg/day ) compared to high doses of olanzapine ( 50 mg/day ) . No patients on olanzapine responded while 20 % responded to clozapine treatment . Olanzapine patients tended to experience higher rates of anticholinergic effects such as dry mouth ( 80 vs. 20 % ) and blurry vision ( 40 vs. 0 % ) . Clozapine-treated patients had higher rates of sialorrhea ( 80 vs. 10 % ) , sweating ( 50 vs. 10 % ) , dyspepsia ( 70 vs. 30 % ) , and lethargy ( 90 vs. 60 % ) . Neither treatment was associated with significant akathisia . Liver enzyme elevation and lipids were higher with clozapine treatment . Mean weight gain in the initial 8 weeks was 3.4 kg for olanzapine and 1.2 kg for clozapine . High doses of olanzapine during 8 weeks of treatment did not increase lipids and liver enzymes like clozapine did . Olanzapine at 50 mg/day may be associated with more anticholinergic effects and weight gain than clozapine The large numbers of partial clozapine responders represent a major therapeutic challenge . Unfortunately , there are no clear data to support how best to treat these patients . This study examines the efficacy and safety of adjunctive risperidone in a well-defined treatment-resistant population optimally treated with clozapine .  A total of 69 in patients and out patients with DSM-IV schizophrenia or schizoaffective disorder entered a 16-week double-blind , placebo-controlled , r and omized clinical trial . Of them , 33 participants were r and omized to risperidone and 36 were r and omized to placebo .  There was no significant group difference in the predefined response criteria . There were modest group differences for Brief Psychiatric Rating Scale ( BPRS ) positive symptoms , which were significant in the completer analysis ( F=5.70 ; df=1 , 70.3 ; p=0.02 ; ES=0.27 ) but not the intent-to-treat ( ITT ) analyses ( F=3.01 ; df=1 , 77.5 ; p=0.09 ; ES=0.19 ) . A similar pattern was found for the BPRS total score , with the completer analysis showing a significant improvement in the risperidone group ( F=5.21 ; df=1 , 64.9 ; p=0.03 ; ES=0.27 ) , whereas the ITT analysis was not significant ( F=3.52 ; df=1 , 71.3 ; p=0.06 ; ES=0.22 ) . In addition , there was a small , but significant , group difference for negative symptoms , as measured by the SANS total score , which favored the risperidone group ( F=5.67 ; df=1 , 78.7 ; p=0.02 ; ES=0.24 ) . There were no significant group differences on safety measures , including neuropsychological test and extrapyramidal symptom scores . A significant elevation of prolactin in the risperidone group was observed . The study results suggest that adjunctive risperidone may have a modest benefit for treatment-resistant clozapine patients . The study results are discussed in the context of previous double-blind studies of adjunctive risperidone . ( clinical trials.gov , trial number : NCT00056498 ) OBJECTIVE Inadequate response to clozapine poses a substantial problem in the pharmaco-therapy of refractory schizophrenia . This r and omized , double-blind , placebo-controlled study evaluated the efficacy and safety of aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia . METHOD Patients with DSM-IV schizophrenia who had a history of treatment failure or partial response to long-term clozapine treatment were recruited . A total of 62 patients with either a baseline Brief Psychiatric Rating Scale ( BPRS ) score of at least 35 or more than 2 Schedule for Assessment of Negative Symptoms ( SANS ) global rating item scores of at least 3 were r and omly assigned to double-blind augmentation treatment with either aripiprazole ( 5 - 30 mg/day ) or placebo over 8 weeks . The primary outcome measure was change in BPRS total score from baseline . The study was conducted between December 1 , 2005 , and December 10 , 2006 . RESULTS There was no significant difference in the primary outcome measure between the 2 groups . In secondary analyses , improvement was significantly greater with aripiprazole treatment than with placebo for negative symptoms assessed by both the BPRS negative symptom sub-scale and the SANS total score but not for positive symptoms . Prolactin and triglyceride levels were significantly lower in the aripiprazole group than in the placebo group . No significant differences between the 2 groups were observed in adverse effects , including extrapyramidal symptoms and serum glucose levels . CONCLUSION Although aripiprazole augmentation of clozapine did not lead to a significant improvement of total symptom severity in schizophrenia , a favorable change in the negative symptom domain was observed OBJECTIVE Quetiapine is often prescribed at higher than approved doses . We investigated the safety , tolerability , and efficacy of quetiapine > 800 mg/d . METHOD A trial was carried out from October 2003-September 2005 in 19 referral centers . Patients with DSM-IV schizophrenia or schizoaffective disorder were r and omized on the basis of persistent symptoms of moderate severity ( < 30 % improvement in total Positive and Negative Syndrome Scale score after ≥ 4 weeks of quetiapine ) . The 8 week , double-blind study compared continuation of quetiapine 800 mg/d ( n = 43 ) versus 1,200 mg/d ( n = 88 ) . The primary outcome measure was emergent or worsening parkinsonism ( Simpson-Angus Scale ) . Secondary outcomes were adverse events , metabolic side effects , and symptom severity . RESULTS Mean doses obtained were 799 mg/d and 1,144 mg/d in the 800-mg/d and > 800-mg/d groups , respectively . Emergent or deteriorating parkinsonism in the high-dose group was 3.1 % greater ( 95 % CI , -7.8 % to 14.0 % ; P = .76 ) than in the 800-mg/d group , a value that was within the a priori limit of 16 % defined as noninferiority . Both doses of quetiapine  were safe and well tolerated . Weight gain was greater in the high-dose group ( 1.7 kg over 12 weeks ; ≥ 7 % body weight , n = 11 [ 12.5 % ] ) versus the 800-mg/d group ( 1.1 kg over 12 weeks ; ≥ 7 % body weight , n = 4 [ 9.3 % ] ) . The mean adjusted difference in weight gain ( 1.3 kg ) was greater in the high-dose group ( 95 % CI , 0.0 - 2.5 ; P = .044 ) . Symptom severity declined , with no significant difference between groups . CONCLUSIONS The results did not demonstrate any advantage for use of quetiapine outside the approved dose range . TRIAL REGISTRATION www . clinical trials.gov Identifier : NCT00328978
target: At the time of this review , seven AAPs were available in Canada : aripiprazole clozapine olanzapine paliperidone quetiapine risperidone ziprasidone
background: Schizophrenia is a mental illness that requires lifelong treatment and is associated with symptoms that include hallucinations , delusions , cognitive impairment , disorganized thoughts , social withdrawal , and low motivation .
  Antipsychotic medications are effective at relieving the symptoms of schizophrenia , and they form the foundation of treatment .