We also calculated the mean percentage change by averaging the percentage change from baseline across patients in each treatment group. Mean percentage change from baseline to last visit in the AOM 400 group improved for all 5 Marder factors [25.5% (positive symptoms), 13.8% (negative symptoms), 23.0% (disorganized thought), 9.3% (uncontrolled hostility/excitement), and 23.3% (anxiety/depression)] and for PEC scores (14.1%). In contrast, improvements were not observed with placebo for the uncontrolled hostility/excitement score (worsening of 10.5%) or PEC (worsening of 2.3%), and improvements for the other factors ranged from 5.3% (negative symptoms) to 13.2% (positive symptoms).
Safety and tolerability results, including treatment-emergent adverse events (previously reported12) were consistent with the established AOM 400 safety/tolerability profile. During acute treatment, concomitant benzodiazepine use was similar between groups (83.2% AOM 400; 83.7% placebo), with respective mean ± SD daily doses of 2.24 ± 1.23 mg and 2.40 ± 1.35 mg (lorazepam equivalents). Median (range) duration of benzodiazepine use was also comparable between AOM 400 and placebo [22.0 (1.0–119.0) and 19.0 (1.0–91.0) days, respectively].
The results of this post hoc analysis demonstrated that AOM 400 treatment in patients with schizophrenia experiencing an acute exacerbation of psychotic symptoms provided significant improvements from baseline compared with placebo across all 5 PANSS Marder factors and PEC. Because patients were comparable at study start across symptom domains, these results suggest that AOM 400 effectively treated the continuum of schizophrenia symptoms, including agitation, regardless of the patient's baseline status.
In acute psychiatric settings, the primary goals are to treat positive symptoms and obtain rapid control of disruptive behaviors, such as hostility and agitation. In this analysis, AOM 400 demonstrated a statistically significant improvement in the positive Marder factor domain compared with placebo as early as week 1 that was maintained throughout the study. Aripiprazole once-monthly 400 mg achieved and maintained statistically significant improvements versus placebo in the uncontrolled hostility/excitement Marder factor at week 1. While placebo-treated patients showed negligible score reductions, AOM 400-treated patients had steady improvements from baseline, with the largest differences between treatment groups occurring at weeks 10 and 12.
At the first time point (week 1 postbaseline), significant benefits of AOM 400 with concomitant oral aripiprazole were observed. A 5-day head-to-head study comparing orally administered aripiprazole and olanzapine in acutely psychotic patients gives insight into the speed of response in acute settings, where improvements must be attained within hours or days.19 Daily mean improvement in PEC scores (the primary outcome measure) was seen in both treatment groups at all visits, with no significant differences between groups. By study end, more than half the patients in both treatment groups were considered responders (≥40% reduction in PEC scores). Despite having different activities at the dopamine D2 receptor (aripiprazole: partial agonism; olanzapine: antagonism), aripiprazole showed similar efficacy to olanzapine in treating agitation and positive symptoms in acutely ill patients. This earlier study is of particular relevance because pharmacokinetic data indicate that the first injection of AOM 400 should be accompanied by an overlap with an oral antipsychotic.20 In the acute study reported here, patients in the AOM 400 group took oral aripiprazole for the first 2 weeks of the study; thus, the influence of oral aripiprazole on the rapid effects observed in this post hoc analysis must be considered.14
Aripiprazole has low sedative potential, and its use in schizophrenia is consistent with the principle of managing agitation and other positive symptoms by calming patients rather than sedating them.21 Throughout acute treatment in the current trial, benzodiazepine use was comparable between treatment groups, suggesting that the greater efficacy of AOM 400 versus placebo was not related to sedative effects. A low incidence of sedation-related adverse events was observed in this study in both AOM 400- and placebo-treated patients,12 which further supports the conclusion that psychotic symptoms can be controlled independently from sedation. It should be noted that agitation improvement was observed despite a higher incidence of akathisia with AOM 400 compared with placebo.
These findings are also consistent with those of a pooled post hoc analysis of 5 double-blind trials of oral aripiprazole, 4 to 6 weeks in duration, conducted in patients hospitalized for acute exacerbations of schizophrenia or schizoaffective disorder.14 In that analysis, oral aripiprazole achieved significantly greater improvements from baseline versus placebo in all 5 PANSS Marder factors, and significant differences were seen by week 1 in all factors except depression/anxiety, for which significant differences were seen from week 2.
For patients with schizophrenia experiencing an acute psychotic episode, it is necessary to consider long-term outcomes in addition to short-term treatment goals from the time of the acute treatment phase. Once positive symptoms and agitation have been controlled, clinical focus turns to symptoms that have an ongoing detrimental effect on daily life. Negative symptoms affect long-term functional outcomes22,23 and have an unfavorable impact on self-esteem.24 Several atypical antipsychotics (eg, clozapine, risperidone, olanzapine) have shown significant improvements in negative symptoms compared with placebo and haloperidol. In this study, significant improvements with AOM 400 versus placebo were seen on the negative symptom Marder factor scores from week 1 through the end of the study, with notable score reductions at week 12.
Disorganized thinking may be one of the most debilitating aspects of schizophrenia,25 and cognitive function is often severely affected.26 Cognitive deficits, anxiety, and depression each compound negative symptoms, contributing to amotivation, social withdrawal, and poor functional outcomes.27 In this post hoc analysis, patients achieved significantly better results with AOM 400 versus placebo in disorganized thought and anxiety/depression factors throughout the study.
This analysis was based on data from a robustly designed, large, randomized, placebo-controlled, double-blind study. Although week 10 (primary endpoint) completion rates were higher in the AOM 400 (64%) versus the placebo (49%) groups,12 there was concordance between the MMRM, LOCF, and OC analyses, suggesting that the differences in discontinuation rates did not bias the results. Discontinuations due to lack of efficacy, which can lead to efficacy assessment biases, were far greater in the placebo than the AOM 400 group.12
Limitations include (1) the post hoc nature of the analyses reported here, because the study was not powered to detect differences on Marder factors or the PEC, and (2) the lack of correction for multiple comparisons. However, since all P values were less than 0.001 at weeks 10 and 12, the chance of type 1 error was minimal. Also, the comparator was placebo rather than an active comparator; greater symptom improvements are expected when an antipsychotic agent is compared with placebo.
In patients experiencing acute schizophrenia exacerbation, treatment with AOM 400 and concomitant oral aripiprazole in the first 2 weeks was efficacious and demonstrated a rapid onset of action across all domains of the illness conceptualized by the PANSS Marder factors and the PEC scores. Aripiprazole once-monthly 400 mg provided efficacy across a range of symptom domains in patients receiving once-monthly dosing, which has important implications for both short- and long-term outcomes.
Editorial support for development of this article was provided by C4 MedSolutions, LLC (Yardley, Pa), a CHC Group company, and funded by Otsuka Pharmaceutical Commercialization & Development, Inc, and H. Lundbeck A/S. The authors wish to acknowledge Dr David Tano at the University of Calgary Cumming School of Medicine and Veronique Littmann at Otsuka Canada for assistance with initiating and addressing conceptual issues with the article.
AUTHOR DISCLOSURE INFORMATION
Funding for this study and for writing assistance was provided by Otsuka Pharmaceutical Development & Commercialization, Inc, and H. Lundbeck A/S.
Ross Baker, Na Jin, Pamela Perry, Timothy Peters-Strickland, Raymond Sanchez, and Robert D. McQuade are employees of Otsuka Pharmaceutical Development & Commercialization, Inc. Anna Eramo is an employee of Lundbeck LLC. Peter Hertel is an employee of H. Lundbeck A/S. Maia Miguelez is an employee of Otsuka Canada. Zahinoor Ismail has received honoraria for lectures by The Canadian Psychiatric Association, Calgary Foothills Primary Care Network, Calgary West Central Primary Care Network, Canadian Conference on Dementia, Alberta College of Family Physicians, and the University of British Columbia; and for consultancy for Janssen, Lundbeck, Otsuka, Pfizer, and Sunovion. John Kane has received honoraria for lectures and/or consulting from Alkermes, Amgen, Bristol-Myers Squibb, Cephalon, Eisai, Boehringer Ingelheim, Eli Lilly, Forrest, Genentech, Intracellular Therapeutics, Janssen, Johnson & Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Pierre Fabre, Proteus, Reviva, Roche, Sunovion, and Targacept; and is a shareholder of MedAvante.
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Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
aripiprazole once-monthly; schizophrenia; PANSS Marder factors