Changes in positive and negative syndrome scale-derived hostility factor in adolescents with schizophrenia treated with aripiprazole: post hoc analysis of randomized clinical trial data.

INTRODUCTION: This post hoc analysis evaluated the effects of aripiprazole on Positive and Negative Syndrome Scale (PANSS) Hostility factor scores in adolescents with schizophrenia. METHODS: In total, 302 adolescents (13-17 years) with schizophrenia were enrolled in a 6-week, multicenter, double-blind, randomized, placebo-controlled trial comparing aripiprazole (10 or 30 mg/day) with placebo. The PANSS was the primary outcome measure. To determine the effect of aripiprazole on hostility, a post hoc analysis of the PANSS Hostility factor and individual items was performed. RESULTS: Aripiprazole was superior to placebo in reducing PANSS Hostility factor scores in adolescents with schizophrenia. After 6 weeks, aripiprazole 10 mg/day and aripiprazole 30 mg/day showed a statistically significant improvement versus placebo (-3.0, -3.7, versus -2.1; p < 0.05; last observation carried forward [LOCF]) in the PANSS Hostility factor. For aripiprazole 30 mg/day, statistically significant separation from placebo was evident from week 3 through week 6 and at week 6 for aripiprazole 10 mg/day. Individual PANSS Hostility, Uncooperativeness, and Poor Impulse Control Items showed statistically significant improvement with aripiprazole 30 mg/day over placebo at end point. CONCLUSIONS: This post hoc analysis shows that aripiprazole (10 and 30 mg/day) is an effective treatment for hostility symptoms in adolescents with schizophrenia. Clinical trials information: ClinicalTrials.gov identifier: NCT00102063.

Evaluation of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder: a post hoc analysis of pooled data from short- and long-term aripiprazole trials.

The objective of this article is to assess the clinical characteristics of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder receiving aripiprazole, haloperidol, olanzapine, or placebo. We conducted post hoc analyses of pooled safety data from trials in patients with schizophrenia, schizoaffective disorder, and bipolar I disorder. Outcome measures included the incidence of akathisia, time to onset, duration, severity, and discontinuation due to akathisia, concomitant use of benzodiazepines and/or anticholinergics, Barnes Akathisia Rating Scale (BARS) scores, and the correlation between antipsychotic efficacy and akathisia. The results for schizophrenia and schizoaffective disorder were as follows: akathisia in 9% of aripiprazole- and 6% of placebo-treated patients; 12.5% of aripiprazole- versus 24% of haloperidol-treated patients; 11% of aripiprazole- versus 6% of olanzapine-treated patients. Bipolar I disorder: akathisia in 18% of aripiprazole- and 5% of placebo-treated patients. The clinical characteristics of akathisia were similar between each data set, regardless of disease. Akathisia was generally mild-to-moderate in severity. Discontinuation due to akathisia was low in both the schizophrenia trials (aripiprazole 0.3%; placebo 0%; aripiprazole 0.9%; haloperidol 2.3%; aripiprazole 1.2%; olanzapine 0.2%) and the bipolar trials (aripiprazole 2.3%; placebo 0%). Treatment-emergent akathisia was not associated with a poorer clinical response. In conclusion, akathisia with aripiprazole occurred early in treatment, was mild-to-moderate in severity, led to few study discontinuations, and did not compromise therapeutic efficacy.

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.

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 randomly 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 randomly 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 populations-for example, in cases of hyperprolactinemia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00325689.

An open-label study of aripiprazole: pharmacokinetics, tolerability, and effectiveness in children and adolescents with conduct disorder.

OBJECTIVES: This study evaluated flexible-dose pharmacokinetics, safety, and effectiveness of aripiprazole in children and adolescents with conduct disorder (CD). METHODS: This open-label, 15-day, three-center study with an optional 36-month extension enrolled a total of 23 patients: 12 children (6-12 years) and 11 adolescents (13-17 years) with CD and a score of 2-3 on the Rating of Aggression Against People and/or Property (RAAPP). Initially, the protocol used the following dosing: subjects <25 kg, 2 mg/day; subjects 25-50 kg, 5 mg/day; subjects >50-70 kg, 10 mg/day; and subjects >70 kg, 15 mg/day. Due to vomiting and sedation, this schedule was revised to: <25 kg, 1 mg/day; 25-50 kg, 2 mg/day; >50-70 kg, 5 mg/day; and >70 kg, 10 mg/day. RESULTS: Aripiprazole pharmacokinetics were linear, and steady state appeared to be attained within 14 days. Both groups demonstrated improvements in RAAPP scores and Clinical Global Impressions-Severity (CGI-S) scores. Adverse events were similar to the known profile for aripiprazole in adults. CONCLUSION: The pharmacokinetics of aripiprazole in children and adolescents are linear and comparable with those in adults. Aripiprazole was generally well-tolerated in patients with CD, particularly after protocol adjustments, with improvements in aggressive behavior.

Akathisia: an updated review focusing on second-generation antipsychotics.

OBJECTIVE: To provide a brief description of the pathophysiology of akathisia, the challenges of diagnosing and treating this condition, and potential associated clinical issues. Also, to provide a review of the literature on the incidence of drug-induced akathisia associated with the use of second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs). DATA SOURCES: English-language literature with no date restrictions cited in PubMed was searched for the keywords akathisia, placebo, neuroleptic, or haloperidol, and the generic names of SGAs (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole). STUDY SELECTION: Limits were set to search clinical trials, meta-analyses, or randomized controlled trials reviewing data from adult schizophrenia or bipolar disorder clinical trials. Studies including SGA comparisons with placebo and with FGAs, and also between SGAs themselves, were selected. Studies that specifically assessed akathisia (either subjectively or objectively or both) were included. Studies reporting generalized results pertaining to extrapyramidal symptoms (EPS) were excluded. DATA EXTRACTION: The incidence of akathisia, EPS rating scores, and required medications for the management of movement disorders were reviewed. DATA SYNTHESIS: Seventy-seven trials were included in the comparative review. Akathisia was observed with the use of all the SGAs. The akathisia incidence reported in bipolar disorder trials was generally higher compared with schizophrenia trials. The incidence reported for FGAs was consistently higher than that reported for SGAs, regardless of the patient population studied. CONCLUSION: Akathisia remains a concern with the use of SGAs. More accurate and standardized evaluations are required for a better understanding of the nature and incidence of akathisia.

The acute efficacy of aripiprazole across the symptom spectrum of schizophrenia: a pooled post hoc analysis from 5 short-term studies.

OBJECTIVE: To evaluate the efficacy of aripiprazole across a range of symptoms-positive, negative, disorganized thought, depression/anxiety, and hostility-in schizophrenia and schizoaffective disorder. METHOD: Pooled data were analyzed from 5 short-term, double-blind, multicenter studies (published between 1997 and 2007) involving patients hospitalized with acute exacerbation of schizophrenia (5 studies) or schizoaffective disorder (2 studies) and randomly assigned to aripiprazole (N = 875), haloperidol (N = 193), risperidone (N = 95), or placebo (N = 406). Aripiprazole doses ranged from 2 to 30 mg/day. Patients receiving the ineffective 2-mg dose were excluded from the primary analyses presented here. Factor analysis of Positive and Negative Syndrome Scale (PANSS) data was used to evaluate changes from baseline with aripiprazole on 5 symptom factors-positive, negative, disorganized thought, depression/anxiety, and hostility-in 2 population subsets-schizophrenia and schizoaffective disorder. Pairwise comparisons were made as follows for schizophrenia: aripiprazole versus placebo in all 5 studies; aripiprazole, haloperidol, and placebo in 3 studies; and aripiprazole, risperidone, and placebo in 1 study. Patients with schizoaffective disorder in 2 studies were included in the comparison of aripiprazole and placebo. RESULTS: Aripiprazole was significantly better than placebo in improving all 5 PANSS factor scores from baseline (each p < .001) in the schizophrenia dataset. In schizoaffective disorder, aripiprazole was significantly better than placebo for the improvement of positive (p

The efficacy, safety, and tolerability of aripiprazole for the treatment of schizoaffective disorder: results from a pooled analysis of a sub-population of subjects from two randomized, double-blind, placebo-controlled, pivotal trials.

BACKGROUND: Schizoaffective disorder shares clinical characteristics with schizophrenia and affective disorders, with patients experiencing concurrent manic, mixed, or depressive episodes during psychosis. Because efficacy may be better in schizoaffective disorder than schizophrenia, this post-hoc analysis examines the efficacy, safety, and tolerability of aripiprazole in patients with schizoaffective disorder. METHOD: Data were obtained from a sub-sample of subjects with schizoaffective disorder (randomized: aripiprazole n=123, placebo n=56) who participated in two 4-week, multicenter, double-blind trials of subjects with schizophrenia or schizoaffective disorder. Aripiprazole was administered at fixed doses of 15 mg/day, 20 mg/day, or 30 mg/day. Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS) Total score, and the Positive, Negative, and General Psychopathology subscale scores. Safety and tolerability evaluations included incidence of treatment-emergent adverse events and extrapyramidal symptom assessments (SAS, BARS, and AIMS), and metabolic profile changes including weight and BMI. RESULTS: A significantly greater improvement from baseline to endpoint was observed with aripiprazole compared with placebo on the PANSS Total (-15.9 vs. -3.4; p=0.038) and PANSS Positive subscale (-4.6 vs. -1.0; p=0.027). Differences between treatments were not significant for the PANSS Negative subscale score (-3.7 vs. -1.2; p=0.15) or PANSS General Psychopathology subscale score (-8.3 vs. -3.1; p=0.06). There were no statistically significant differences at endpoint between groups in the mean change from baseline to endpoint in weight, glucose, or total cholesterol, or on SAS, BARS, or AIMS scores. There was a statistically significant decrease in prolactin in subjects treated with aripiprazole compared with placebo (-5.6 vs. -1.3, p<0.001). CONCLUSION: Aripiprazole was efficacious and well tolerated in patients with schizoaffective disorder.

The efficacy of aripiprazole in the treatment of multiple symptom domains in patients with acute schizophrenia: a pooled analysis of data from the pivotal trials.

OBJECTIVE: To examine the efficacy of aripiprazole across symptoms in patients with acute exacerbation of schizophrenia or schizoaffective disorder. METHODS: Data were pooled from five, 4-6-week acute studies. PANSS Total, Positive, Negative, and General Psychopathology Subscale improvements were analyzed, as well as all 30 individual PANSS items. RESULTS: Aripiprazole had statistically significant decreases versus placebo on PANSS subscales at Week 4, similar to those seen with haloperidol. Aripiprazole-treated patients also showed significant decreases versus placebo in 26 of the 30 PANSS items (all p<0.05). CONCLUSION: Aripiprazole demonstrates statistically and clinically significant efficacy across a range of symptoms in schizophrenia.