Agitation is a major concern in schizophrenia owing to the risk of its escalation into aggression and violence.1,2 Hostility and aggression in schizophrenia are etiologically heterogeneous and may develop as a consequence of uncontrolled psychosis, increased impulsivity, or comorbid psychopathy.3 Agitation is a common reason for emergency department visits among patients with schizophrenia and requires immediate management to prevent harm to the patient and those around them.1,2
The management of agitation and hostility represents a significant treatment challenge in schizophrenia.1,3 Evaluating the cause of agitation can be problematic because agitated patients are often uncooperative.2 The traditional restrain and sedate approach to managing agitation can be harmful to the patient and to the therapeutic alliance, and current guidelines recommend calming techniques together with offering noninvasive pharmacotherapy (rather than injections), whenever possible.1,2
Brexpiprazole is a serotonin-dopamine activity modulator that acts as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors, and as an antagonist at serotonin 5-HT2A and noradrenaline α1B/α2C receptors, all with subnanomolar affinity.4 The efficacy and safety of brexpiprazole for the treatment of adults with acute schizophrenia have been demonstrated in two 6-week, randomized, controlled studies.5,6 In an open-label maintenance study, brexpiprazole was generally well tolerated for up to 52 weeks in patients with schizophrenia and was associated with continued improvement in efficacy measures.7 Brexpiprazole is approved in various countries and regions, including the United States, Canada, Australia, Japan, and the European Union, for the treatment of schizophrenia in adults. Brexpiprazole is also approved in the United States, Canada, Saudi Arabia, Honduras, and Mexico as an adjunctive therapy to antidepressants for the treatment of major depressive disorder in adults.
The aim of this post hoc analysis was to evaluate the efficacy of brexpiprazole compared with placebo for reducing agitation and hostility in patients hospitalized with an acute exacerbation of schizophrenia and to investigate the independence of any reduction in hostility with regard to positive symptoms, akathisia, and somnolence, as has been done in similar analyses of other antipsychotic medications.8–11 In addition, longer-term changes in agitation and hostility among patients treated with brexpiprazole were investigated. Finally, safety was assessed in subgroups with and without hostility.
MATERIALS AND METHODS
Study Design and Patients
This was a post hoc analysis of data from 2 short-term, randomized, double-blind, placebo-controlled studies of brexpiprazole in patients with acute schizophrenia (Vector [NCT01396421] and Beacon [NCT01393613])5,6 and a long-term, open-label extension study in schizophrenia (Zenith [NCT01397786]).7 The studies were conducted at sites across Asia, Europe, Latin America, and North America between July 2011 and January 2014 (short-term studies), and between September 2011 and February 2016 (long-term study). The studies were conducted in compliance with the International Conference on Harmonisation Good Clinical Practice Consolidated Guideline and in accordance with the Declaration of Helsinki. The protocols were approved by independent ethics committees, and all patients provided written informed consent to participate after procedures and possible side effects were explained to them.
Full descriptions of the study designs and selection criteria have been published.5–7 In brief, the short-term studies included patients aged 18 to 65 years experiencing an acute exacerbation of schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria) and who would benefit from hospitalization or continued hospitalization. Patients were excluded if they had a first episode of schizophrenia, a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision Axis I diagnosis other than schizophrenia, clinically significant tardive dyskinesia, or substance abuse or dependence in the previous 180 days. The studies had similar designs, comprising a 14-day screening phase, a 6-week double-blind treatment phase, and a 30-day follow-up phase. In Vector, eligible patients were randomized to placebo or fixed doses of 0.25, 2, or 4 mg/d of oral brexpiprazole (2:1:2:2). In Beacon, eligible patients were randomized to placebo or fixed doses of 1, 2, or 4 mg/d of oral brexpiprazole (3:2:3:3). Brexpiprazole was titrated in the 2 mg groups such that patients received 1 mg/d for the first 4 days and then 2 mg/d from the fifth day onwards. In the 4 mg group, the same pattern was followed until the eighth day, when the dose was increased to 4 mg/d. Patients were hospitalized throughout the double-blind treatment phase.
Patients who completed the short-term studies were eligible to roll over into the long-term, open-label study (Zenith). Zenith also enrolled de novo patients and those who completed a maintenance treatment study; these patients were not included in the present post hoc analyses. Patients in Zenith received flexibly dosed 1 to 4 mg/d of oral brexpiprazole for up to 52 weeks (study amended to 26 weeks toward the end; this amendment only applied to the 11.2% of patients who enrolled after the date of the amendment).
In all 3 studies, brexpiprazole was administered as monotherapy. Use of other psychotropic agents was prohibited, including antipsychotics, antidepressants, mood stabilizers (ie, lithium and anticonvulsants), and benzodiazepines (except specific benzodiazepines for the control of agitation and insomnia).
The primary efficacy analysis in both short-term studies was the mean change in Positive and Negative Syndrome Scale (PANSS)12 total score from baseline (randomization) to week 6. The PANSS was administered at baseline and weeks 1, 2, 3, 4, 5, and 6. In the long-term study, efficacy was assessed as a secondary objective using the PANSS (administered at open-label weeks 1, 2, 4, and 8, at 6-weekly intervals until week 44, and at week 52). The PANSS raters were qualified and experienced clinicians who were trained and certified in PANSS administration for these studies. For the original studies, there were 192 qualified PANSS raters in Vector, 213 in Beacon, and 574 in Zenith.
In this post hoc analysis, agitation was assessed using the PANSS Excited Component (EC) (comprising the following items: excitement [P4], hostility [P7], tension [G4], uncooperativeness [G8], and poor impulse control [G14]13), as used in similar analyses of other antipsychotic medications.10,11,14–17 The PANSS-EC is scored from 5 (agitation absent) to 35 (extreme agitation). Hostility was assessed using the PANSS hostility item (P7) (defined as “verbal and nonverbal expressions of anger and resentment, including sarcasm, passive-aggressive behavior, verbal abuse, and assaultiveness”), as used in similar analyses of other antipsychotic medications.9–11,18–22 As with all PANSS items, P7 (hostility) is scored from 1 (absent) to 7 (extreme).
Safety was assessed by the incidence of treatment-emergent adverse events (TEAEs).
Post Hoc Categorization of Hostility Status
A P7 cutoff of 3 points or greater (at least mild hostility) was used to define the presence of hostility at baseline, as done in similar analyses of other antipsychotic medications.10,18
In addition, a P7 cutoff of 2 points or greater (at least minimal hostility), as used in other similar analyses,9–11,21,22 was used for supportive analyses presented in Supplemental Digital Content 1, https://links.lww.com/JCP/A614.
Patients without a baseline PANSS assessment were excluded from the analyses.
Short-term data were pooled for the placebo groups, the brexpiprazole 2 mg groups, and the brexpiprazole 4 mg groups. The brexpiprazole 0.25 mg and 1 mg groups, intended to evaluate the lower dose range, were not included in the post hoc analysis. Within these pooled subgroups, efficacy analyses were performed in the sample of patients who received at least 1 dose of study medication and had at least 1 postbaseline PANSS assessment. Safety analyses were performed in the sample of patients who received at least 1 dose of study medication.
Baseline was defined as the randomization visit. Least squares (LS) mean changes from baseline (with standard errors) in PANSS-EC score were derived using a mixed model repeated measures (MMRM) approach with fixed effect factors of protocol, trial center within protocol, treatment, visit, treatment-visit interaction; fixed effect covariates of baseline value and baseline-visit interaction; and with a heterogeneous Toeplitz variance-covariance matrix structure. The LS mean changes from baseline in PANSS hostility item (P7) score were derived using 3 MMRM models, controlling for changes in positive symptoms, akathisia, and somnolence, to test specific antihostility effect, similar to other published analyses of the antihostility effect of antipsychotic medications.8–11 In detail, the 3 MMRM models used the following terms:
- Fixed effect factors of treatment, visit, and treatment-visit interaction; positive symptoms as covariate (sum of PANSS item scores for delusions [P1], conceptual disorganization [P2], hallucinatory behavior [P3], grandiosity [P5], suspiciousness/persecution [P6], and unusual thought content [G9]); and with an unstructured variance-covariance matrix.
- As for model 1, with Barnes Akathisia Rating Scale Global score23 as an additional time-dependent covariate.
- As for model 2, with the presence of somnolence (including hypersomnia and sedation) as a TEAE as an additional time-dependent fixed effect.
Least squares mean differences (LSMDs) were calculated between brexpiprazole and placebo groups on the PANSS-EC and P7 outcomes, with 95% confidence limits (CLs) and P values, using the above MMRM models. All tests were 2-sided at a 5% level. Because of the exploratory nature of the study, correction for multiple comparisons was not performed.
For long-term analyses, data were combined from the 6-week short-term studies and the 52-week open-label extension study so that a total of up to 58 weeks of brexpiprazole treatment could be investigated. With this treatment duration in mind, the analyses included only those patients in the long-term study who had previously received 2 to 4 mg of brexpiprazole in the short-term studies (ie, patients who previously received placebo or low doses of brexpiprazole were not analyzed).
Baseline was defined as the randomization visit of the short-term studies. Mean changes from baseline in PANSS-EC and P7 scores were summarized using descriptive statistics.
In the short-term studies, after excluding 6 patients with no baseline PANSS assessment, the randomized sample comprised 1094 patients allocated to placebo (n = 366), brexpiprazole 2 mg (n = 366), or brexpiprazole 4 mg (n = 362). All of these patients were treated and formed the safety sample. Excluding patients with no postbaseline PANSS measurements, the efficacy sample comprised 1076 patients.
Of the randomized sample, 556 patients (50.8%) had hostility at baseline as defined by a PANSS hostility item (P7) score of 3 or greater, and 538 patients (49.2%) did not have hostility at baseline. Hostility at baseline did not appear to influence completion rates, which were 65.7% to 72.6% across brexpiprazole subgroups and 60.0% to 62.9% across placebo subgroups (Table 1). Overall, the most common reason for discontinuation among patients receiving brexpiprazole was that the patient withdrew consent (Table 1). A greater proportion of patients discontinued because of adverse events in the placebo subgroups than in the brexpiprazole subgroups.
Baseline demographic and clinical characteristics were generally similar between treatment groups (Table 1). Hostility at baseline did not appear to depend on demographic and clinical characteristics, except for PANSS total score, which was higher among patients with hostility (98.6–100.4) than those without hostility (90.7–92.2). On average, patients were markedly ill at baseline, as shown by mean Clinical Global Impressions — Severity of illness24 scores of around 5 in all subgroups.
The long-term sample comprised 346 patients who rolled over from the short-term studies, of whom 170 (49.1%) had hostility at baseline of the short-term studies (P7 score ≥3).
PANSS-EC Score Change in the Efficacy Sample
The LS mean change in PANSS-EC score from baseline to week 6 in the efficacy sample is presented in Figure 1A. At week 6, advantages over placebo were seen for brexpiprazole 2 mg (LSMD, −0.69 [95% CLs, −1.28, −0.11]; P = 0.020) and for brexpiprazole 4 mg (−1.11 [−1.70, −0.53]; P = 0.0002). For brexpiprazole 4 mg, benefits over placebo (P < 0.01) were seen at all weekly visits (Fig. 1A).
The mean change in PANSS-EC score from baseline to open-label week 52 in the efficacy sample is presented in Figure 1B. With long-term brexpiprazole treatment, PANSS-EC score changed by a mean (SD) of −5.2 (4.2) points from baseline to open-label week 26 (n = 193) and by −5.8 (3.9) points from baseline to open-label week 52 (n = 144). The majority of the improvement occurred during the first 6 to 10 weeks of treatment, and the benefits were maintained over 58 weeks (Fig. 1B).
PANSS-EC Score Change in Patients With Hostility at Baseline (P7 Score ≥3)
The LS mean change in PANSS-EC score from baseline to week 6 in patients with hostility at baseline (P7 score ≥3) is presented in Figure 1C. At week 6, brexpiprazole 4 mg was superior to placebo in reducing PANSS-EC score from baseline at week 6 (LSMD, −1.03 [95% CLs, −1.92, −0.14]; P = 0.024), whereas brexpiprazole 2 mg showed numerical improvement (−0.63 [−1.54, 0.28]; P = 0.18).
The mean change in PANSS-EC score from baseline to open-label week 52 in patients with hostility at baseline (P7 score ≥3) is presented in Figure 1D. With long-term brexpiprazole treatment, patients with hostility at baseline showed further improvement in PANSS-EC score, changing from baseline by a mean (SD) of −7.3 (3.9) points to open-label week 26 (n = 95) and by −8.2 (3.3) points to open-label week 52 (n = 69). As was observed in the efficacy sample, the majority of improvement occurred during the first 6 to 10 weeks of treatment, and benefits were maintained over 58 weeks (Fig. 1D).
P7 (Hostility) Score Change in Patients With Hostility at Baseline (P7 Score ≥3)
The LS mean change in P7 score from baseline to week 6 in patients with hostility at baseline (P7 score ≥3) is presented in Figure 2. Brexpiprazole 2 mg (LSMD, −0.27 [95% CLs, −0.53, −0.01]; P = 0.038) and brexpiprazole 4 mg (−0.34 [−0.59, −0.09]; P = 0.0080) were superior to placebo in reducing P7 score at week 6, independent of improvement in positive symptoms (MMRM model 1). Similar benefits were observed when also adjusting for akathisia (MMRM model 2), for brexpiprazole 2 mg (−0.26 [−0.51, 0.00]; P = 0.048) and for brexpiprazole 4 mg (−0.33 [−0.57, −0.08]; P = 0.010). Finally, comparable benefits were observed when also adjusting for akathisia and somnolence (MMRM model 3), for brexpiprazole 2 mg (−0.26 [−0.51, 0.00]; P = 0.049) and for brexpiprazole 4 mg (−0.33 [−0.58, −0.08]; P = 0.0098).
With long-term brexpiprazole treatment, patients with hostility at baseline showed further improvement in P7 score, changing from baseline by a mean (SD) of −1.9 (1.1) points to open-label week 26 (n = 95) and by −2.1 (1.0) points to open-label week 52 (n = 69).
In the short-term studies, 789 randomized patients (72.1%) had hostility at baseline as defined by a P7 score of 2 or greater. In this subgroup, brexpiprazole 4 mg was superior to placebo at week 6 with regard to change in PANSS-EC score and P7 score; brexpiprazole 2 mg showed numerical advantages over placebo. Further improvements in PANSS-EC score and P7 score were observed with long-term brexpiprazole treatment (see Supplemental Digital Content 1, https://links.lww.com/JCP/A614, and Supplementary Figures 1 and 2, Supplemental Digital Contents 2 and 3, https://links.lww.com/JCP/A615 and https://links.lww.com/JCP/A616, for details).
Safety and Tolerability
TEAEs in Patients With/Without Hostility at Baseline (P7 Score ≥3)
In patients with hostility at baseline, the proportion of patients with at least 1 TEAE over 6 weeks was comparable between the placebo (55.9%), brexpiprazole 2 mg (61.0%), and brexpiprazole 4 mg (60.1%) subgroups. A similar incidence of TEAEs was also seen in patient subgroups without hostility at baseline (54.1%–61.1%) (Table 2).
Across all treatment groups, the incidence of akathisia over 6 weeks was higher among patients with hostility at baseline (6.7%) than those without hostility at baseline (4.1%). The highest incidence of akathisia was among patients with hostility at baseline who received the 4 mg dose of brexpiprazole (8.6%) (Table 2). The incidences of sedation and somnolence were low (each <5%) in all treatment subgroups, with and without hostility at baseline. Schizophrenia as a TEAE (ie, worsening of the underlying disease) was more common in the placebo subgroups than in the brexpiprazole subgroups (Table 2).
In patients with a P7 score of 2 or greater at baseline, a similar pattern of TEAEs was observed (see Supplemental Digital Content 1, https://links.lww.com/JCP/A614, and Supplementary Table 1, Supplemental Digital Content 4 https://links.lww.com/JCP/A617, for details).
In this sample of patients hospitalized with an acute exacerbation of schizophrenia, brexpiprazole 4 mg/d consistently improved symptoms of agitation and hostility over 6 weeks compared with placebo (P < 0.05), as shown by the change from baseline in PANSS-EC and PANSS hostility item (P7) scores. Brexpiprazole 2 mg/d also showed benefits over placebo (P < 0.05), with a smaller effect on PANSS-EC score and a comparable effect on P7 score to the 4 mg dose over 6 weeks. Patients continued into long-term, open-label brexpiprazole treatment, during which further improvement in agitation and hostility was observed and maintained over 58 weeks. Although the analyses described here were not prespecified and should be considered as hypothesis generating, these data suggest that brexpiprazole should be further studied as a potential treatment option for patients with agitation or hostility in schizophrenia.
Other randomized, controlled studies (or post hoc analyses thereof) have shown benefits for various atypical antipsychotics in the treatment of agitation and/or hostility in patients with schizophrenia.8–11,14–20,25,26 Over 6 weeks, brexpiprazole 4 mg had a comparable within-group PANSS-EC score change in the present study with that observed in prior studies of aripiprazole (in a subgroup with baseline PANSS-EC score ≥14) and lurasidone,14,17 and the LSMD of brexpiprazole 4 mg versus placebo approached those seen in studies of cariprazine and lurasidone.10,17 Brexpiprazole 2 mg and 4 mg also showed comparable within-group improvement in P7 score over 6 weeks to cariprazine and lurasidone in patients with baseline P7 scores of 3 and greater, and 2 and greater9,10 and much greater within-group improvement in P7 score than aripiprazole over 4 weeks (although patients in the aripiprazole study were not stratified by baseline P7 score).20 The authors are not aware of any long-term agitation or hostility data for aripiprazole, cariprazine, or lurasidone.
On the PANSS hostility item, improvement associated with brexpiprazole in the short-term studies was specific, that is, independent of change in positive symptoms, akathisia, and somnolence. Most antipsychotics are associated with activating and/or sedating adverse effects,27 which would be expected to influence agitation and hostility outcomes. An analysis of acute schizophrenia studies found that the number needed to harm versus placebo for akathisia was 11 for lurasidone, 15 for cariprazine, 31 for aripiprazole, and 112 for brexpiprazole.27 The numbers needed to harm versus placebo for somnolence were 20 for lurasidone, 34 for aripiprazole, 65 for cariprazine (including sedation and other related terms), and −271 for brexpiprazole.27 Thus, by indirect comparison, brexpiprazole seems to be neither activating nor sedating, thereby potentially offering a benefit over aripiprazole, cariprazine, and lurasidone.
Short- and long-term studies have shown that brexpiprazole is generally well tolerated among patients with schizophrenia.28 No new safety or tolerability concerns were observed in the present analysis among patients with hostility. Rates of akathisia as a TEAE over 6 weeks were slightly higher among patients with hostility at baseline than those without, regardless of treatment group. Among patients with hostility, the incidence of akathisia over 6 weeks was greater in the brexpiprazole 4 mg group than in the 2 mg group (8.6% vs 5.2%), indicating a possible dose effect. Rates of agitation as a TEAE were generally comparable between groups, and the incidences of sedation and somnolence were low in all treatment groups.
This study is limited by its post hoc nature and, as an exploratory analysis that requires confirmation in a prespecified study, by the lack of correction for multiple comparisons. There was no active comparator, meaning that direct comparisons with another antipsychotic cannot be made. Patients were not specifically selected because of a history of agitated and hostile behavior, and hostility, a complex behavior, was measured using a single item only. The study is also limited by the exclusion of patients with substance abuse or dependence in the previous 180 days, because recent substance misuse seems to increase the risk of violence in patients with schizophrenia (hostility and violence are strongly linked).29,30 Finally, rescue medication for agitation (specified benzodiazepines) was permitted during the studies, adding a potential confounder to the results.
In conclusion, the results of this analysis in a large sample of over a thousand patients suggest that brexpiprazole has the potential to be an efficacious and well-tolerated treatment for agitation and hostility in schizophrenia.
Writing support was provided by Chris Watling, PhD, assisted by his colleagues at Cambridge Medical Communication Ltd (Cambridge, UK), and funded by Otsuka Pharmaceutical Development & Commercialization Inc and H. Lundbeck A/S.
AUTHOR DISCLOSURE INFORMATION
L.C., in the past 12 months, has consulted for Acadia, Alkermes, Allergan, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva, and Vanda; has acted as a speaker for Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva; owns stocks (small number of shares of common stock) in Bristol-Myers Squibb, Eli Lilly, J & J, Merck, and Pfizer (purchased >10 years ago); and has received royalties from Wiley (Editor-in-Chief, International Journal of Clinical Practice), UpToDate (reviewer), and Springer Healthcare (book). J.O., L.S., R.A.B., and C.W. are full-time employees of Otsuka Pharmaceutical Development & Commercialization Inc (Princeton, NJ). S.R.M. is a full-time employee of H. Lundbeck A/S (Valby, Denmark).
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