- Email: [email protected]
21– A 6-week study of the efficacy and tolerability of aripiprazole in pediatric patients with schizophrenia
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199 parametric contrast of increasing difficulty compared to controls. The gradient of ventral striatal and prefrontal activation were significantly associated with reversal errors in bipolar patients. Conclusions: Patients with bipolar I disorder show abnormalities in ventral frontostriatal systems whereas patients with schizophrenia showed dorsal prefrontal abnormalities. This finding suggests that there may be underlying differences in the neural substrates of each disorder. Acknowledgement: This study and two of the investigators (AMM and SML) were supported by the Dr Mortimer and Theresa Sackler Foundation during the period of data collection. Dr McIntosh is currently supported by the Health Foundation through a Clinician Scientist Fellowship. doi:10.1016/j.schres.2007.12.086
41
with greater placebo improvements in the later clinical trials. Sample differences other than baseline severity of illness did not contribute to the larger placebo response seen in the more recent clinical trials. Acknowledgement: Supported by Ortho-McNeil Janssen Scientific Affairs, LLC. doi:10.1016/j.schres.2007.12.087
21– A 6-WEEK STUDY OF THE EFFICACY AND TOLERABILITY OF ARIPIPRAZOLE IN PEDIATRIC PATIENTS WITH SCHIZOPHRENIA W.H. Carson 1, M. Nyilas 1, R.A. Forbes 1, A. Pikalov 1, R.D. McQuade 1, R. Owen 2, S. Todorov 3, J. Fraizer 4.
Bipolar/Schizophrenia Comparisons – Treatment 20 – PLACEBO RESPONSE IN CONTROLLED CLINICAL TRIALS OF PATIENTS WITH SCHIZOPHRENIA: A DECADE OF DIFFERENCES L. Alphs 1, I. Turkoz 1, C. Bossie 1, C. Canuso 1, M. Kujawa 1. 1
Ortho-McNeil Janssen Scientific Affairs, LLC, United States
Presenting Author details: [email protected] 1125 Trenton-Harbourton Road, 08560 Titusville, United States, Tel.: +1 609 730 3482. Background: To examine the difference in patients' response to placebo in antipsychotic clinical trials over time. Methods: Data from published, placebo-controlled, acute schizophrenia trials of risperidone (1 international, 2 US) conducted from the mid-late 1980s through early-mid 1990s (“Earlier Trials”) were compared with those of similar trials performed with paliperidone extended-release (2 international, 1 US) conducted at least a decade later (“Later Trials”). Placebo responses evaluated (at Week 6 and Endpoint) included mean change from baseline in total Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI-S) scores, proportions of responders and non-responders (based upon PANSS changes) and adverse events. Results: Similar rates of completion were observed (44.6% and 40.5% in Earlier and Later Trials, p = 0.3213). Greater placebo improvements measured with total PANSS were observed in Later vs. Earlier Trials at Week 6 (p b 0.001), but not at Endpoint (p = 0.884). Placebo responder rates were significantly different between the Trials at Week 6 (p = 0.0115) and Endpoint (p = 0.0140). CGI-S improvements were greater at Week 6 in the Later vs. Earlier Trials (p b 0.001). Later Trials included more females, were of greater ethnic diversity, and enrolled subjects with shorter durations of illness but greater aggregate symptom severity. Adverse events incidences were similar (64% and 67% in Earlier and Later Trials); although a greater incidence of cardiac disorders was noted (1.3% vs. 12.3%). Conclusions: This preliminary analysis of placebo responses suggests that completion of 6 weeks of treatment was associated
1 Otsuka Pharmaceutical Development and Commercialization, Princeton, NJ, USA 2 Bristol Myers-Squibb, Wallingford, CT, USA 3 Multifunctinal Hospital for Active Treatment, Varna, Bulgaria 4 Cambridge Health Alliance, Somerville, MA, USA
Presenting Author details: [email protected] 100 Overlook Ctr, Ste. 3, 08540 Princeton, United States, Tel.: +1 609 452 5663; fax: +1 240 399 6204. Background: Optimal management of pediatric patients with schizophrenia is limited by the lack of data from double-blind, placebo-controlled trials. Clinicians often refer to data from adult studies when making treatment decisions in this patient population. The safety and efficacy of aripiprazole, a next-generation antipsychotic approved for use in adults with schizophrenia and bipolar disorder was investigated in adolescents with schizophrenia. Methods: This is a double-blind, placebo-controlled 6-week study of aripiprazole for treatment of adolescent patients with schizophrenia. 302 youths, ages 13–17 years old with a DSM-IV diagnosis of schizophrenia were randomized 1:1:1 to placebo or aripiprazole 10 mg and 30 mg, reached after 5 or 11 days of titration, respectively. The primary endpoint was mean change from baseline on Positive and Negative Syndrome Scale (PANSS) Total score at week 6. Secondary endpoints included PANSS Positive and Negative subscales, Clinical Global Impressions—Improvement scale (CGI-I), Children's Global Assessment Scale (CGAS) and P-QLES-Q Overall item score. Safety measures included incidence of adverse events (AEs) and discontinuation due to AEs. Extrapyramidal symptom (EPS) related events were assessed using Abnormal Involuntary Movement Scale (AIMS), Simpson Angus Extrapyramidal Symptoms Rating Scale (SAS) and Barnes Akathisia Rating Scale (BARS). Weight change, ECG, and prolactin were also measured. Results: Eighty-five percent of patients completed the 6-week study. At end of study, both 10 mg and 30 mg groups showed significant differences from placebo on the PANSS Total score, with significant differences observed at Week 1 (30 mg). Both dose groups showed significant improvement on PANSS positive, CGI-I scales, CGAS score, and P-QLES-Q Overall score and the 10 mg dose group was superior to placebo on the PANSS negative score. AEs were generally mild to moderate in severity, with
42
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
approximately 5% of aripiprazole patients discontinuing due to AEs. The most common AEs were extrapyramidal disorder, somnolence, and tremor. Weight gain and changes in prolactin were minimal. Conclusions: Both 10 mg and 30 mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. EPS was the most common adverse event.
rates for aripiprazole 10 mg and 30 mg were 45% and 64%, respectively, both of which were significantly higher (p b .01 and p b .0001) than placebo (26%). Conclusions: Aripiprazole 10 mg and 30 mg doses were significantly superior to placebo in acute treatment of children and adolescents with bipolar disorder. doi:10.1016/j.schres.2007.12.089
doi:10.1016/j.schres.2007.12.088
22 – ACUTE EFFICACY OF ARIPIPRAZOLE FOR THE TREATMENT OF BIPOLAR I DISORDER IN PEDIATRIC PATIENTS
23 – ANALYSIS OF PSYCHIATRIC HOSPITALIZATION AFTER INITIATION OF ORAL ANTIPSYCHOTIC TREATMENT FOR SCHIZOPHRENIA J. Diels 1, K. Trakas 2, D. Nicholl 3, G. Nuyts 3.
1
1
1
1
W.H. Carson , M. Nyilas , R.A. Forbes , A. Pikalov , R.D. McQuade 1, S. Ivanova 1, R. Owen 2, L. Ginsberg 3, K.D. Wagner 4. 1 Otsuka Pharmaceutical Development and Commercialization, Princeton, NJ, USA 2 Bristol Myers-Squibb, Wallingford, CT, USA 3 Red Oak Psychiatry Associates, PA Houston, TX, USA 4 University of Texas Medical Branch, Galveston, TX, USA
Presenting Author details: [email protected] 100 Overlook Ctr, Ste. 3, 08540 Princeton, United States, Tel.: +1 609 452 5663; fax: +1 240 399 6204. Background: There is limited published data from pediatric bipolar trials with which to guide appropriate treatment decisions. The purpose of this study was to assess the efficacy of aripiprazole in the treatment of pediatric bipolar I disorder. Methods: Two hundred and ninety-six youths, ages 10–17 years with a DSM-IV diagnosis of bipolar I disorder, manic or mixed episode w/wo psychotic features were randomized 1:1:1 to receive placebo or aripiprazole 10 mg or 30 mg, reached after a 5- or 13day titration, respectively. This is a 4-week, double-blind trial conducted on an outpatient basis (option for inpatient hospitalization, if needed). No concomitant psychotropic medications were allowed, with exception of prn benzodiazepines and anticholinergics. The primary efficacy endpoint was change from baseline to week 4 on the Young Mania Rating Scale (YMRS) total score. Secondary efficacy endpoints included change from baseline on Children's Global Assessment Scale (CGAS) score, Clinical Global Impression Scale – Bipolar Version (CGIS-BP) severity score, Children's Depression Rating Scale – Revised (CRRS-R) score, General Behavior Inventory Scale (GBI) score and Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) score. Response was defined as N50% reduction from baseline in the YMRS total score. Results: Eighty percent of patients completed this study. At week 1, aripiprazole 10 mg and 30 mg showed significant superiority to placebo (p b .05) on the primary endpoint which continued through the end of the 4-week trial (p b .0001). Compared to placebo, there was significantly greater improvement for both doses of aripiprazole on secondary measures of CGAS, CGIS-BP severity score, GBI, ADHD-RS-IV. Response
1
Health Economics, Johnson and Johnson Pharmaceutical Services, Beerse, Belgium 2 Health Economics, Janssen-Ortho, Toronto, Canada 3 Health Economics, Johnson and Johnson Pharmaceutical Services, Raritan, USA Presenting Author details: [email protected] Turnhoutseweg 30, B-2340 Beerse, Belgium, Tel.: +32 14 603443; fax: +32 14 605425. Background: Efficacy and side-effect profiles amongst antipsychotics are key considerations in optimizing patient care. This analysis tested the difference between two groups of agents: those rated as more highly effective [1], olanzapine and risperidone, versus those with potential higher tolerability, aripiprazole, quetiapine and ziprasidone. Methods: Patients diagnosed with schizophrenia (ICD-9-CM code) in the year prior to initiating a new antipsychotic treatment between Jan 02 and Mar 05, were identified in Pharmetrics, a large US outpatient insurance claims database with regionally representative coverage. Impact of initiating treatment was assessed individually and for: (i) risperidone or olanzapine and (ii) aripiprazole, quetiapine or ziprasidone. The proportion of patients hospitalized for psychiatric reasons in the year following initiation of treatment was analyzed using a logistic regression. Frequency (stays) and duration (days) of psychiatric hospitalization were examined using generalized gamma regression (GLM). All analyses were carried out on an intent-to-treat population and adjusted for potential confounders. Results: 2261 patients initiated on risperidone (54%) or olanzapine (46%) and 2571 patients initiated on aripiprazole (35%), quetiapine (40%) or ziprasidone (25%) met inclusion criteria. After adjustment for differences in patient characteristics and treatment history, risk of psychiatric hospitalization was significantly higher in patients initiated with aripiprazole, quetiapine or ziprasidone as measured by the proportion of patients hospitalized (OR = 1.19, 95% CI = 1.02–1.40; p = 0.029), adjusted mean number of stays (0.59 vs. 0.51, p b 0.0001) and days (6.69 vs. 5.16, p b 0.0001) in hospital compared to patients initiated on risperidone or olanzapine. Conclusions: This study suggests a separation by clinical outcomes within atypical agents of efficacy versus tolerability agents.
41
with greater placebo improvements in the later clinical trials. Sample differences other than baseline severity of illness did not contribute to the larger placebo response seen in the more recent clinical trials. Acknowledgement: Supported by Ortho-McNeil Janssen Scientific Affairs, LLC. doi:10.1016/j.schres.2007.12.087
21– A 6-WEEK STUDY OF THE EFFICACY AND TOLERABILITY OF ARIPIPRAZOLE IN PEDIATRIC PATIENTS WITH SCHIZOPHRENIA W.H. Carson 1, M. Nyilas 1, R.A. Forbes 1, A. Pikalov 1, R.D. McQuade 1, R. Owen 2, S. Todorov 3, J. Fraizer 4.
Bipolar/Schizophrenia Comparisons – Treatment 20 – PLACEBO RESPONSE IN CONTROLLED CLINICAL TRIALS OF PATIENTS WITH SCHIZOPHRENIA: A DECADE OF DIFFERENCES L. Alphs 1, I. Turkoz 1, C. Bossie 1, C. Canuso 1, M. Kujawa 1. 1
Ortho-McNeil Janssen Scientific Affairs, LLC, United States
Presenting Author details: [email protected] 1125 Trenton-Harbourton Road, 08560 Titusville, United States, Tel.: +1 609 730 3482. Background: To examine the difference in patients' response to placebo in antipsychotic clinical trials over time. Methods: Data from published, placebo-controlled, acute schizophrenia trials of risperidone (1 international, 2 US) conducted from the mid-late 1980s through early-mid 1990s (“Earlier Trials”) were compared with those of similar trials performed with paliperidone extended-release (2 international, 1 US) conducted at least a decade later (“Later Trials”). Placebo responses evaluated (at Week 6 and Endpoint) included mean change from baseline in total Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI-S) scores, proportions of responders and non-responders (based upon PANSS changes) and adverse events. Results: Similar rates of completion were observed (44.6% and 40.5% in Earlier and Later Trials, p = 0.3213). Greater placebo improvements measured with total PANSS were observed in Later vs. Earlier Trials at Week 6 (p b 0.001), but not at Endpoint (p = 0.884). Placebo responder rates were significantly different between the Trials at Week 6 (p = 0.0115) and Endpoint (p = 0.0140). CGI-S improvements were greater at Week 6 in the Later vs. Earlier Trials (p b 0.001). Later Trials included more females, were of greater ethnic diversity, and enrolled subjects with shorter durations of illness but greater aggregate symptom severity. Adverse events incidences were similar (64% and 67% in Earlier and Later Trials); although a greater incidence of cardiac disorders was noted (1.3% vs. 12.3%). Conclusions: This preliminary analysis of placebo responses suggests that completion of 6 weeks of treatment was associated
1 Otsuka Pharmaceutical Development and Commercialization, Princeton, NJ, USA 2 Bristol Myers-Squibb, Wallingford, CT, USA 3 Multifunctinal Hospital for Active Treatment, Varna, Bulgaria 4 Cambridge Health Alliance, Somerville, MA, USA
Presenting Author details: [email protected] 100 Overlook Ctr, Ste. 3, 08540 Princeton, United States, Tel.: +1 609 452 5663; fax: +1 240 399 6204. Background: Optimal management of pediatric patients with schizophrenia is limited by the lack of data from double-blind, placebo-controlled trials. Clinicians often refer to data from adult studies when making treatment decisions in this patient population. The safety and efficacy of aripiprazole, a next-generation antipsychotic approved for use in adults with schizophrenia and bipolar disorder was investigated in adolescents with schizophrenia. Methods: This is a double-blind, placebo-controlled 6-week study of aripiprazole for treatment of adolescent patients with schizophrenia. 302 youths, ages 13–17 years old with a DSM-IV diagnosis of schizophrenia were randomized 1:1:1 to placebo or aripiprazole 10 mg and 30 mg, reached after 5 or 11 days of titration, respectively. The primary endpoint was mean change from baseline on Positive and Negative Syndrome Scale (PANSS) Total score at week 6. Secondary endpoints included PANSS Positive and Negative subscales, Clinical Global Impressions—Improvement scale (CGI-I), Children's Global Assessment Scale (CGAS) and P-QLES-Q Overall item score. Safety measures included incidence of adverse events (AEs) and discontinuation due to AEs. Extrapyramidal symptom (EPS) related events were assessed using Abnormal Involuntary Movement Scale (AIMS), Simpson Angus Extrapyramidal Symptoms Rating Scale (SAS) and Barnes Akathisia Rating Scale (BARS). Weight change, ECG, and prolactin were also measured. Results: Eighty-five percent of patients completed the 6-week study. At end of study, both 10 mg and 30 mg groups showed significant differences from placebo on the PANSS Total score, with significant differences observed at Week 1 (30 mg). Both dose groups showed significant improvement on PANSS positive, CGI-I scales, CGAS score, and P-QLES-Q Overall score and the 10 mg dose group was superior to placebo on the PANSS negative score. AEs were generally mild to moderate in severity, with
42
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
approximately 5% of aripiprazole patients discontinuing due to AEs. The most common AEs were extrapyramidal disorder, somnolence, and tremor. Weight gain and changes in prolactin were minimal. Conclusions: Both 10 mg and 30 mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. EPS was the most common adverse event.
rates for aripiprazole 10 mg and 30 mg were 45% and 64%, respectively, both of which were significantly higher (p b .01 and p b .0001) than placebo (26%). Conclusions: Aripiprazole 10 mg and 30 mg doses were significantly superior to placebo in acute treatment of children and adolescents with bipolar disorder. doi:10.1016/j.schres.2007.12.089
doi:10.1016/j.schres.2007.12.088
22 – ACUTE EFFICACY OF ARIPIPRAZOLE FOR THE TREATMENT OF BIPOLAR I DISORDER IN PEDIATRIC PATIENTS
23 – ANALYSIS OF PSYCHIATRIC HOSPITALIZATION AFTER INITIATION OF ORAL ANTIPSYCHOTIC TREATMENT FOR SCHIZOPHRENIA J. Diels 1, K. Trakas 2, D. Nicholl 3, G. Nuyts 3.
1
1
1
1
W.H. Carson , M. Nyilas , R.A. Forbes , A. Pikalov , R.D. McQuade 1, S. Ivanova 1, R. Owen 2, L. Ginsberg 3, K.D. Wagner 4. 1 Otsuka Pharmaceutical Development and Commercialization, Princeton, NJ, USA 2 Bristol Myers-Squibb, Wallingford, CT, USA 3 Red Oak Psychiatry Associates, PA Houston, TX, USA 4 University of Texas Medical Branch, Galveston, TX, USA
Presenting Author details: [email protected] 100 Overlook Ctr, Ste. 3, 08540 Princeton, United States, Tel.: +1 609 452 5663; fax: +1 240 399 6204. Background: There is limited published data from pediatric bipolar trials with which to guide appropriate treatment decisions. The purpose of this study was to assess the efficacy of aripiprazole in the treatment of pediatric bipolar I disorder. Methods: Two hundred and ninety-six youths, ages 10–17 years with a DSM-IV diagnosis of bipolar I disorder, manic or mixed episode w/wo psychotic features were randomized 1:1:1 to receive placebo or aripiprazole 10 mg or 30 mg, reached after a 5- or 13day titration, respectively. This is a 4-week, double-blind trial conducted on an outpatient basis (option for inpatient hospitalization, if needed). No concomitant psychotropic medications were allowed, with exception of prn benzodiazepines and anticholinergics. The primary efficacy endpoint was change from baseline to week 4 on the Young Mania Rating Scale (YMRS) total score. Secondary efficacy endpoints included change from baseline on Children's Global Assessment Scale (CGAS) score, Clinical Global Impression Scale – Bipolar Version (CGIS-BP) severity score, Children's Depression Rating Scale – Revised (CRRS-R) score, General Behavior Inventory Scale (GBI) score and Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) score. Response was defined as N50% reduction from baseline in the YMRS total score. Results: Eighty percent of patients completed this study. At week 1, aripiprazole 10 mg and 30 mg showed significant superiority to placebo (p b .05) on the primary endpoint which continued through the end of the 4-week trial (p b .0001). Compared to placebo, there was significantly greater improvement for both doses of aripiprazole on secondary measures of CGAS, CGIS-BP severity score, GBI, ADHD-RS-IV. Response
1
Health Economics, Johnson and Johnson Pharmaceutical Services, Beerse, Belgium 2 Health Economics, Janssen-Ortho, Toronto, Canada 3 Health Economics, Johnson and Johnson Pharmaceutical Services, Raritan, USA Presenting Author details: [email protected] Turnhoutseweg 30, B-2340 Beerse, Belgium, Tel.: +32 14 603443; fax: +32 14 605425. Background: Efficacy and side-effect profiles amongst antipsychotics are key considerations in optimizing patient care. This analysis tested the difference between two groups of agents: those rated as more highly effective [1], olanzapine and risperidone, versus those with potential higher tolerability, aripiprazole, quetiapine and ziprasidone. Methods: Patients diagnosed with schizophrenia (ICD-9-CM code) in the year prior to initiating a new antipsychotic treatment between Jan 02 and Mar 05, were identified in Pharmetrics, a large US outpatient insurance claims database with regionally representative coverage. Impact of initiating treatment was assessed individually and for: (i) risperidone or olanzapine and (ii) aripiprazole, quetiapine or ziprasidone. The proportion of patients hospitalized for psychiatric reasons in the year following initiation of treatment was analyzed using a logistic regression. Frequency (stays) and duration (days) of psychiatric hospitalization were examined using generalized gamma regression (GLM). All analyses were carried out on an intent-to-treat population and adjusted for potential confounders. Results: 2261 patients initiated on risperidone (54%) or olanzapine (46%) and 2571 patients initiated on aripiprazole (35%), quetiapine (40%) or ziprasidone (25%) met inclusion criteria. After adjustment for differences in patient characteristics and treatment history, risk of psychiatric hospitalization was significantly higher in patients initiated with aripiprazole, quetiapine or ziprasidone as measured by the proportion of patients hospitalized (OR = 1.19, 95% CI = 1.02–1.40; p = 0.029), adjusted mean number of stays (0.59 vs. 0.51, p b 0.0001) and days (6.69 vs. 5.16, p b 0.0001) in hospital compared to patients initiated on risperidone or olanzapine. Conclusions: This study suggests a separation by clinical outcomes within atypical agents of efficacy versus tolerability agents.