Sheila Assunção-Talbott

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.

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.

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.

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.

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.

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.

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.

COMPARISON OF REMISSION RATES AND TOLERABILITY IN PATIENTS WITH EARLY-EPISODE SCHIZOPHRENIA RECEIVING ARIPIPRAZOLE OR HALOPERIDOL

Introduction: This analysis compared remission rates in patients with early-diagnosed schizophrenia receiving either aripiprazole or haloperidol. Methods: Pooled data from two 52-week, randomized, double-blind, multicenter trials of aripiprazole vs. haloperidol in acutely ill patients with schizophrenia were analyzed. Symptomatic remission was calculated according to RSWG criteria in patients with early-episode schizophrenia (patients mean = 40 years with mean duration of illness = 60 months). Results: Remission rates were significantly higher for early-episode patients treated with aripiprazole compared with haloperidol (38% vs. 22%; p=0.003). Aripiprazole-treated patients achieved remission in a shorter time than haloperidol-treated patients; however, this difference was not statistically significant between the two groups (log rank p=0.1, HR=1.4, 95% CI: 0.9- 2.1). All remitters received significantly lower global clinical ratings than non-remitters (p<0.0001 for both treatments). Aripiprazole was associated with a significantly lower rate of discontinuations due to AEs than haloperidol (10.6% vs. 29.3%; p<0.001) and lower concomitant medication use for EPS (26% vs. 60%; p<0.0001). Conclusions: Acutely ill patients with early-episode schizophrenia treated with aripiprazole demonstrated a significantly higher rate of symptomatic remission compared with haloperidol-treated patients based on RSWG criteria. Aripiprazole was better tolerated, as shown by its lower discontinuation rates due to AEs and lower use of anticholinergics. Although more data are needed, this preliminary post-hoc analysis shows the efficacy and tolerability of aripiprazole in patients with early-episode schizophrenia. Acknowledgements: Supported by Bristol-Myers Squibb and Otsuka.