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Treatment of negative symptoms with olanzapine in comparison with other novel antipsychotic agents
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Oral Session X X I H o w Good Are We in Comparing N e w Antipsychotics?
50 YEARS OF CONTROLLED TRIALS RELEVANT TO THE CARE OF PEOPLE WITH SCHIZOPHRENIA C.E. Adams, B. T h o r n l e y Dr. Clive Adams, Cochrane Schizophrenia Group, Summertown Pavilion, Middle Way, Summertown, Oxford OX2 7LG. UK Objective: To comprehensively survey the quality of intervention studies relevant to the treatment of schizophrenia. Methods: A pilot study surveyed the quality of all trials published in the Archives o f General Psychiatry) This refined techniques necessary for this large study. Data were then reliably extracted from 2000 randomly selected schizophrenia trials (1950 1998). Details of type and date of publication, country of origin, language, study size, treatment setting, participant group, interventions, outcomes and study quality were recorded. Results: Generally, studies have been short (50% < 6 weeks), small (50%<50 participants), poorly reported (1% top score Jadad Scale 2), and there are no improvements over time. 3 Study drop out is increasing (16% in all clozapine studies, 30% in risperidone trials, 42% in olanzapine studies and 58% in quetiapine trials by 6-12 weeks). Over 600 different interventions were studied in the 2000 trials and a total of 640 different rating scales were employed to measure outcome. Conclusions: Half a century of studies of limited quality, duration and clinical utility leave much scope for well planned, conducted and reported trials. Fifty years have been spent undertaking trials that are primarily of value to researchers and regulatory authorities. These explanatory trials will continue into the new millenium. However, large, long randomised studies with broad entry criteria, intervention regimens that allow flexibility, and that report outcomes that are of direct relevance to clinicians and people with schizophrenia should become prevalent. References 1. Ahmed I., Soares K.V.S., Seifas R., Adams C.E. Randomized controlled trials in Archives of General Psychiatry (1959-1995): a prevalence study. Archives of General Psychiatry, 1998, 55, 754 5. 2. Jadad A.R., Moore R.A., Carroll D., Jenkinson C., Reynolds D.J., Gavaghan D.J., McQuay H.J. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials, 1996, 17, 1-12. 3. Thornley B., Adams C.E. Content and quality of 2000 controlled trials in schizophrenia over 50 years. BMJ, 1998, 317, 1181 4.
INPATIENT TREATMENT OF SCHIZOPHRENIA: A STUDY OF TWO LEADING ATYPICAL ANTIPSYCHOTICS G. Laux 1, W. KOnig 1, M. Jones 2 IBezirkskrankenhaus Gabersee. Gabersee 7, 83512 Wasserburg, German)' zJones & Just Pty Ltd., PO Box 55, Mt. Kuring-Gai, N S W 2080, Australia Objectives': To (i) compare the outcomes of two leading atypical antipsychotics and (ii) investigate predictors of clinical outcomes in inpatient treatment. Methods': Data were pooled from a series of retrospective, single centre studies across 11 centres within 5 countries. Only patients with a diagnosis of schizophrenia or schizo-affective disorder were considered. Results: A total of 601 patients received either risperidone ( R IS; n = 290) or olanzapine (OLA; n = 311 ) as first line therapy after admission. There were no baseline differences between both groups. The two products showed equivalent efficacy rates ( R I S : 78%, OLA: 77%; p=0.8) but RIS patients achieved improvement sooner (mean=14 days) than OLA patients (mean=23 days; p=0.0008)*. Mean modal daily doses were 4.9mg (RIS) and 14.9mg (OLA). OLA patients were more expensive (US$) than RIS patients in both daily treatment costs (RIS: mean=3.3$; OLA: mean=6,5$; p=0.0001) and daily all medication costs (RIS: mean=4.2$; OLA: mean= 7.35; p=0.0001). The predictors of clinical outcome were examined for two key parameters, probability of being a responder (logistic regression) and time-to-efficacy (Cox proportional hazards model). A key driver of clinical outcome was concomitant use of other neuroleptics; the higher the concomitant use of other neuroleptics, the lower the probability of good clinical outcome. Conclusion: Risperidone and olanzapine showed similar efficacy profiles overall, but risperidone treated patients achieved efficacy sooner. Treatment with olanzapine was significantly more costly than with risperidone. Concomitant use of other neuroleptics was an important predictor of poor clinical outcome. * Time-to-efficacy was not assessed in the German centers; N - 1 1 4 RIS, N=121 OLA.
TREATMENT OF NEGATIVE SYMPTOMS WITH OLANZAPINE IN COMPARISON WITH OTHER NOVEL ANTIPSYCHOTIC AGENTS S.R. David, K.M. M e e h a n , V.K. Sutton, C.C. Taylor Lilly Research Laboratories, Eli Lilly and Company, Indianapolis', USA Negative symptoms of schizophrenia, such as apathy, lack of motivation, and social withdrawal, greatly affect the ability
39
of patients to interact and integrate into the community. This report presents data from two double-blind clinical trials on the negative symptom profile of olanzapine compared to atypical antipsychotic agents, risperidone (6 months; N = 339) and clozapine (18 weeks; N = 180). Effects on negative symptoms were assessed using the mean change from baseline to endpoint on the Scale for the Assessment of Negative Symptoms (SANS), and the negative subscores of the Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS). On both the SANS and the BPRS negative subscore, olanzapine consistently demonstrated statistical superiority over risperidone in treating negative symptoms after 6 months (SANS, p=0.02 and BPRSNEo, p=0.29), while numerically superior on the PANSS negative subscore. In comparison to clozapine, olanzapine did not demonstrate a statistically significant difference in reduction of negative symptoms as measured by PANSS and BPRS negative subscores. However, as measured by both scales, olanzapine consistently had a numerical advantage over clozapine. The lack of statistical significance of the observed clinical effect can be explained by reduced power due to a sample size powered to detect differences in overall symptomatology. In conclusion, compared to alternative atypical antipsychotic therapies, olanzapine was statistically superior to risperidone and as effective as clozapine in the treatment of negative symptoms.
compared to haloperidol (p~<0.01) and fluphenazine ( p = 0.004). Against atypical comparators, olanzapine was statistically superior to clozapine (p = 0.006), and numerically superior to risperidone on the SAS. In 3 of 5 conventional comparator studies, there was a significantly lower incidence in severity of dyskinetic events with olanzapine compared to haloperidol (p ~<0.011 ), as measured by the AIMS. Olanzapine was numerically superior to fluphenazine in decreasing AIMS scores. Against atypical comparators, olanzapine produced numerically greater improvements than clozapine. In conclusion, olanzapine generally produced greater improvement in EPS than alternative antipsychotics, resulting in a more satisfactory safety profile and better treatment outcome.
EFFICACY OF ARIPIPRAZOLE IN PSYCHOTIC DISORDERS: COMPARISON WITH H A L O P E R I D O L A N D PLACEBO J. Kane, G. Ingenito*, M. Ali* Hillside Hospital, Glen Oaks', NY, USA and Otsuka America Pharmaceutical Inc. *, Rockville, MD, USA
C H A N G E IN POSITIVE SYMPTOMS WITH OLANZAPINE COMPARED TO OTHER ANTIPSYCHOTIC AGENTS S.R. David, C.C. Taylor, K.M. Meehan Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA Extrapyramidal symptoms (EPS) - - akathisia, parkinsonism, and tardive dyskinesia - - are serious and common side effects of neuroleptic treatment. This report presents global data from 8 clinical trials (N= 3270) on the EPS profile of olanzapine (8 studies; 2.5 to 25mg/day; n=2131) compared to both conventional (haloperidol [5 studies; 5 to 20mg/day; n=852] and fluphenazine [ 1 study; 6 to 21 mg/day; n = 30]) and atypical (risperidone [1 study; 4 to 12mg/day; n = 167] and clozapine [1 study; 200 to 600mg/day; n=90]) antipsychotics. Improvement was assessed using mean change from baseline to endpoint on the Barnes or Hillside Akathisia Scale, the Simpson-Angus Scale (SAS), and the Abnormal Involuntary Movement Scale (AIMS). In 4 of 5 conventional comparator studies, akithisia scores were significantly decreased with olanzapine compared to haloperidol (Barnes, p~<0.007) and fluphenazine (Hillside, p = 0.017 ). Against atypical comparators, olanzapine produced numerically greater akathisia improvements than risperidone at 8 weeks, but not 6 months. In 4 of 5 conventional comparator studies, SAS scores were significantly decreased with olanzapine
Aripiprazole, a novel agent with a unique spectrum of pharmacologic activities, is in development for the treatment of the symptoms associated with psychotic disorders. The first Phase III clinical trial was a double-blind, four-week comparison of two fixed doses of aripiprazole ( 15 and 30 mg), haloperidol (10 mg) and placebo in over 400 hospitalized patients with a DSM-IV diagnosis of acute relapse of schizophrenia or schizoaffective disorder. Efficacy of both doses of aripiprazole and haloperidol were significantly superior to placebo (change in PANSS-total, BPRS-total, LOCF; p<0.01). However, responder analysis (30% decrease from baseline in PANSStotal at last visit) indicated both doses of aripiprazole to be significantly better than placebo (p <0.05), while the response rate for haloperidol was not significantly different from placebo (p < 0.1 ). Aripiprazole was well tolerated; the number of subjects discontinuing due to adverse events was less than placebo and haloperidol. No clinically meaningful increase in QTc prolongation was observed in aripiprazole treated subjects. Extrapyramidal symptomatology with aripiprazole was not different from placebo. Additionally, fewer patients treated with aripiprazole received at least one administration of benztropine (10.8-16.8%) than those treated with haloperidol (36.0%), The incidence of clinically significant increases in prolactin levels with aripiprazole was comparable to placebo and substantially less than haloperidol. The incidence of clinically significant increases in body weight with aripiprazole was less than with haloperidol. This study clearly demonstrates the clinical efficacy and tolerability of aripiprazole and suggests it may be an important future therapeutic option.
Oral Session X X I H o w Good Are We in Comparing N e w Antipsychotics?
50 YEARS OF CONTROLLED TRIALS RELEVANT TO THE CARE OF PEOPLE WITH SCHIZOPHRENIA C.E. Adams, B. T h o r n l e y Dr. Clive Adams, Cochrane Schizophrenia Group, Summertown Pavilion, Middle Way, Summertown, Oxford OX2 7LG. UK Objective: To comprehensively survey the quality of intervention studies relevant to the treatment of schizophrenia. Methods: A pilot study surveyed the quality of all trials published in the Archives o f General Psychiatry) This refined techniques necessary for this large study. Data were then reliably extracted from 2000 randomly selected schizophrenia trials (1950 1998). Details of type and date of publication, country of origin, language, study size, treatment setting, participant group, interventions, outcomes and study quality were recorded. Results: Generally, studies have been short (50% < 6 weeks), small (50%<50 participants), poorly reported (1% top score Jadad Scale 2), and there are no improvements over time. 3 Study drop out is increasing (16% in all clozapine studies, 30% in risperidone trials, 42% in olanzapine studies and 58% in quetiapine trials by 6-12 weeks). Over 600 different interventions were studied in the 2000 trials and a total of 640 different rating scales were employed to measure outcome. Conclusions: Half a century of studies of limited quality, duration and clinical utility leave much scope for well planned, conducted and reported trials. Fifty years have been spent undertaking trials that are primarily of value to researchers and regulatory authorities. These explanatory trials will continue into the new millenium. However, large, long randomised studies with broad entry criteria, intervention regimens that allow flexibility, and that report outcomes that are of direct relevance to clinicians and people with schizophrenia should become prevalent. References 1. Ahmed I., Soares K.V.S., Seifas R., Adams C.E. Randomized controlled trials in Archives of General Psychiatry (1959-1995): a prevalence study. Archives of General Psychiatry, 1998, 55, 754 5. 2. Jadad A.R., Moore R.A., Carroll D., Jenkinson C., Reynolds D.J., Gavaghan D.J., McQuay H.J. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials, 1996, 17, 1-12. 3. Thornley B., Adams C.E. Content and quality of 2000 controlled trials in schizophrenia over 50 years. BMJ, 1998, 317, 1181 4.
INPATIENT TREATMENT OF SCHIZOPHRENIA: A STUDY OF TWO LEADING ATYPICAL ANTIPSYCHOTICS G. Laux 1, W. KOnig 1, M. Jones 2 IBezirkskrankenhaus Gabersee. Gabersee 7, 83512 Wasserburg, German)' zJones & Just Pty Ltd., PO Box 55, Mt. Kuring-Gai, N S W 2080, Australia Objectives': To (i) compare the outcomes of two leading atypical antipsychotics and (ii) investigate predictors of clinical outcomes in inpatient treatment. Methods': Data were pooled from a series of retrospective, single centre studies across 11 centres within 5 countries. Only patients with a diagnosis of schizophrenia or schizo-affective disorder were considered. Results: A total of 601 patients received either risperidone ( R IS; n = 290) or olanzapine (OLA; n = 311 ) as first line therapy after admission. There were no baseline differences between both groups. The two products showed equivalent efficacy rates ( R I S : 78%, OLA: 77%; p=0.8) but RIS patients achieved improvement sooner (mean=14 days) than OLA patients (mean=23 days; p=0.0008)*. Mean modal daily doses were 4.9mg (RIS) and 14.9mg (OLA). OLA patients were more expensive (US$) than RIS patients in both daily treatment costs (RIS: mean=3.3$; OLA: mean=6,5$; p=0.0001) and daily all medication costs (RIS: mean=4.2$; OLA: mean= 7.35; p=0.0001). The predictors of clinical outcome were examined for two key parameters, probability of being a responder (logistic regression) and time-to-efficacy (Cox proportional hazards model). A key driver of clinical outcome was concomitant use of other neuroleptics; the higher the concomitant use of other neuroleptics, the lower the probability of good clinical outcome. Conclusion: Risperidone and olanzapine showed similar efficacy profiles overall, but risperidone treated patients achieved efficacy sooner. Treatment with olanzapine was significantly more costly than with risperidone. Concomitant use of other neuroleptics was an important predictor of poor clinical outcome. * Time-to-efficacy was not assessed in the German centers; N - 1 1 4 RIS, N=121 OLA.
TREATMENT OF NEGATIVE SYMPTOMS WITH OLANZAPINE IN COMPARISON WITH OTHER NOVEL ANTIPSYCHOTIC AGENTS S.R. David, K.M. M e e h a n , V.K. Sutton, C.C. Taylor Lilly Research Laboratories, Eli Lilly and Company, Indianapolis', USA Negative symptoms of schizophrenia, such as apathy, lack of motivation, and social withdrawal, greatly affect the ability
39
of patients to interact and integrate into the community. This report presents data from two double-blind clinical trials on the negative symptom profile of olanzapine compared to atypical antipsychotic agents, risperidone (6 months; N = 339) and clozapine (18 weeks; N = 180). Effects on negative symptoms were assessed using the mean change from baseline to endpoint on the Scale for the Assessment of Negative Symptoms (SANS), and the negative subscores of the Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS). On both the SANS and the BPRS negative subscore, olanzapine consistently demonstrated statistical superiority over risperidone in treating negative symptoms after 6 months (SANS, p=0.02 and BPRSNEo, p=0.29), while numerically superior on the PANSS negative subscore. In comparison to clozapine, olanzapine did not demonstrate a statistically significant difference in reduction of negative symptoms as measured by PANSS and BPRS negative subscores. However, as measured by both scales, olanzapine consistently had a numerical advantage over clozapine. The lack of statistical significance of the observed clinical effect can be explained by reduced power due to a sample size powered to detect differences in overall symptomatology. In conclusion, compared to alternative atypical antipsychotic therapies, olanzapine was statistically superior to risperidone and as effective as clozapine in the treatment of negative symptoms.
compared to haloperidol (p~<0.01) and fluphenazine ( p = 0.004). Against atypical comparators, olanzapine was statistically superior to clozapine (p = 0.006), and numerically superior to risperidone on the SAS. In 3 of 5 conventional comparator studies, there was a significantly lower incidence in severity of dyskinetic events with olanzapine compared to haloperidol (p ~<0.011 ), as measured by the AIMS. Olanzapine was numerically superior to fluphenazine in decreasing AIMS scores. Against atypical comparators, olanzapine produced numerically greater improvements than clozapine. In conclusion, olanzapine generally produced greater improvement in EPS than alternative antipsychotics, resulting in a more satisfactory safety profile and better treatment outcome.
EFFICACY OF ARIPIPRAZOLE IN PSYCHOTIC DISORDERS: COMPARISON WITH H A L O P E R I D O L A N D PLACEBO J. Kane, G. Ingenito*, M. Ali* Hillside Hospital, Glen Oaks', NY, USA and Otsuka America Pharmaceutical Inc. *, Rockville, MD, USA
C H A N G E IN POSITIVE SYMPTOMS WITH OLANZAPINE COMPARED TO OTHER ANTIPSYCHOTIC AGENTS S.R. David, C.C. Taylor, K.M. Meehan Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA Extrapyramidal symptoms (EPS) - - akathisia, parkinsonism, and tardive dyskinesia - - are serious and common side effects of neuroleptic treatment. This report presents global data from 8 clinical trials (N= 3270) on the EPS profile of olanzapine (8 studies; 2.5 to 25mg/day; n=2131) compared to both conventional (haloperidol [5 studies; 5 to 20mg/day; n=852] and fluphenazine [ 1 study; 6 to 21 mg/day; n = 30]) and atypical (risperidone [1 study; 4 to 12mg/day; n = 167] and clozapine [1 study; 200 to 600mg/day; n=90]) antipsychotics. Improvement was assessed using mean change from baseline to endpoint on the Barnes or Hillside Akathisia Scale, the Simpson-Angus Scale (SAS), and the Abnormal Involuntary Movement Scale (AIMS). In 4 of 5 conventional comparator studies, akithisia scores were significantly decreased with olanzapine compared to haloperidol (Barnes, p~<0.007) and fluphenazine (Hillside, p = 0.017 ). Against atypical comparators, olanzapine produced numerically greater akathisia improvements than risperidone at 8 weeks, but not 6 months. In 4 of 5 conventional comparator studies, SAS scores were significantly decreased with olanzapine
Aripiprazole, a novel agent with a unique spectrum of pharmacologic activities, is in development for the treatment of the symptoms associated with psychotic disorders. The first Phase III clinical trial was a double-blind, four-week comparison of two fixed doses of aripiprazole ( 15 and 30 mg), haloperidol (10 mg) and placebo in over 400 hospitalized patients with a DSM-IV diagnosis of acute relapse of schizophrenia or schizoaffective disorder. Efficacy of both doses of aripiprazole and haloperidol were significantly superior to placebo (change in PANSS-total, BPRS-total, LOCF; p<0.01). However, responder analysis (30% decrease from baseline in PANSStotal at last visit) indicated both doses of aripiprazole to be significantly better than placebo (p <0.05), while the response rate for haloperidol was not significantly different from placebo (p < 0.1 ). Aripiprazole was well tolerated; the number of subjects discontinuing due to adverse events was less than placebo and haloperidol. No clinically meaningful increase in QTc prolongation was observed in aripiprazole treated subjects. Extrapyramidal symptomatology with aripiprazole was not different from placebo. Additionally, fewer patients treated with aripiprazole received at least one administration of benztropine (10.8-16.8%) than those treated with haloperidol (36.0%), The incidence of clinically significant increases in prolactin levels with aripiprazole was comparable to placebo and substantially less than haloperidol. The incidence of clinically significant increases in body weight with aripiprazole was less than with haloperidol. This study clearly demonstrates the clinical efficacy and tolerability of aripiprazole and suggests it may be an important future therapeutic option.