ORIGINAL CONTRIBUTION
Effect of Brexpiprazole on Agitation and Hostility in
Patients With Schizophrenia
Post Hoc Analysis of Short- and Long-Term Studies
Leslie Citrome, MD, MPH,* John Ouyang, PhD,† Lily Shi, MD, MS,† Stine R. Meehan, PhD,‡
Ross A. Baker, PhD, MBA,§ and Catherine Weiss, PhD||
Downloaded from https://journals.lww.com/psychopharmacology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD327SBzrFI0+nPGaUwcz9dOIhx3JuWop/LCo+JR5hxf1M= on 10/28/2019
Abstract:
Background: Managing agitation and hostility represents a significant
treatment challenge in schizophrenia. The aim of this analysis was to eval-
uate the short- and long-term efficacy of brexpiprazole for reducing agita-
tion and hostility in schizophrenia.
Methods: This was a post hoc analysis of data from two 6-week, ran-
domized, double-blind, placebo-controlled studies (ClinicalTrials.gov
identifiers, NCT01396421 and NCT01393613) and a 52-week, open-label,
extension study (NCT01397786). In the short-term studies, 1094 patients
received placebo, 2 mg/d of brexpiprazole, or 4 mg/d of brexpiprazole;
346 brexpiprazole-treated patients rolled over into the long-term study
and received 1 to 4 mg/d of brexpiprazole. Agitation was assessed using
the Positive and Negative Syndrome Scale (PANSS) Excited Component
(EC), and hostility was assessed using the PANSS hostility item (P7).
Results: Brexpiprazole improved PANSS-EC score over 6 weeks, with
least squares mean differences versus placebo of −0.69 (95% confidence
limits, −1.28, −0.11) for 2 mg/d (P = 0.020) and −1.11 (−1.70, −0.53) for
4 mg/d (P = 0.0002). In the subgroup with hostility at baseline (P7 score
≥3; 50.8% of the randomized sample), least squares mean differences ver-
sus placebo at week 6 on the PANSS-EC were −0.63 (−1.54, 0.28) for
2 mg/d (P = 0.18) and −1.03 (−1.92, −0.14) for 4 mg/d (P = 0.024), and
on P7 (adjusted for positive symptoms) were −0.27 (−0.53, −0.01) for
2 mg/d (P = 0.038) and −0.34 (−0.59, −0.09) for 4 mg/d (P = 0.0080).
The improvements were maintained over 58 weeks. Adverse events were
generally comparable between treatment groups over 6 weeks; the inci-
dence of akathisia among patients with hostility was 5.9% with placebo,
5.2% with 2 mg/d, and 8.6% with 4 mg/d.
Conclusions: Brexpiprazole has the potential to be an efficacious and well-
tolerated treatment for agitation and hostility among patients with schizophrenia.
Key Words: brexpiprazole, agitation, hostility, schizophrenia
(J Clin Psychopharmacol 2019;39: 00–00)
From the *Department of Psychiatry and Behavioral Sciences, New York Med-
ical College, Valhalla, NY; †Biostatistics, Otsuka Pharmaceutical Development
& Commercialization Inc, Princeton, NJ; ‡Medical Affairs, H. Lundbeck A/S,
Valby, Denmark; §CNS Global Medical Affairs, Otsuka Pharmaceutical Devel-
opment & Commercialization Inc, Princeton, NJ; and ||Global Medical Affairs,
Otsuka Pharmaceutical Development & Commercialization Inc, Princeton, NJ.
Received May 10, 2019; accepted after revision August 13, 2019.
Reprints: Leslie Citrome, MD, MPH, 11 Medical Park Dr, Suite 106, Pomona, NY
10970 (e‐mail: citrome@cnsconsultant.com).
This work was supported by Otsuka Pharmaceutical Development &
Commercialization Inc (Princeton, NJ) and H. Lundbeck A/S
(Valby, Denmark).
Supplemental digital content is available for this article. Direct URL citation
appears in the printed text and is provided in the HTML and PDF versions
of this article on the journal’s Web site (www.psychopharmacology.com).
Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the work
provided it is properly cited. The work cannot be changed in any way or
used commercially without permission from the journal.
ISSN: 0271-0749
DOI: 10.1097/JCP.0000000000001113
Journal of Clinical Psychopharmacology • Volume 39, Number 6, November/December 2019
A gitation 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 rea-
son for emergency department visits among patients with schizo-
phrenia and requires immediate management to prevent harm to
the patient and those around them.1,2
The management of agitation and hostility represents a sig-
nificant 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 ap-
proach to managing agitation can be harmful to the patient and
to the therapeutic alliance, and current guidelines recommend
calming techniques together with offering noninvasive pharma-
cotherapy (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 nor-
adrenaline 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 treat-
ment 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 re-
duction in hostility with regard to positive symptoms, akathisia,
and somnolence, as has been done in similar analyses of other an-
tipsychotic 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, ran-
domized, 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
www.psychopharmacology.com 1
Citrome et al Journal of Clinical Psychopharmacology • Volume 39, Number 6, November/December 2019
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 pro-
cedures 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 Diag-
nostic 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, com-
prising a 14-day screening phase, a 6-week double-blind treat-
ment 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 pa-
tients 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 main-
tenance 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 mono-
therapy. Use of other psychotropic agents was prohibited, includ-
ing antipsychotics, antidepressants, mood stabilizers (ie, lithium
and anticonvulsants), and benzodiazepines (except specific ben-
zodiazepines for the control of agitation and insomnia).
Assessments
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 sec-
ondary 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 clini-
cians 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 analy-
ses 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
2 www.psychopharmacology.com
“verbal and nonverbal expressions of anger and resentment, in-
cluding 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 sim-
ilar analyses of other antipsychotic medications.10,18
In addition, a P7 cutoff of 2 points or greater (at least min-
imal hostility), as used in other similar analyses,9–11,21,22 was
used for supportive analyses presented in Supplemental Digital
Content 1, http://links.lww.com/JCP/A614.
Patients without a baseline PANSS assessment were excluded
from the analyses.
Statistical Analyses
Short-Term 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 med-
ication 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 pro-
tocol, 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 symp-
toms, akathisia, and somnolence, to test specific antihostility ef-
fect, similar to other published analyses of the antihostility effect
of antipsychotic medications.8–11 In detail, the 3 MMRM models
used the following terms:
1. Fixed effect factors of treatment, visit, and treatment-visit in-
teraction; 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.
2. As for model 1, with Barnes Akathisia Rating Scale Global
score23 as an additional time-dependent covariate.
3. 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.
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
Journal of Clinical Psychopharmacology • Volume 39, Number 6, November/December 2019 Brexpiprazole's Effect on Agitation

Long-Term Analyses
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 in-
cluded only those patients in the long-term study who had previ-
ously 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.
RESULTS
Patients
Short-Term Analyses
In the short-term studies, after excluding 6 patients with no baseline
PANSS assessment, the randomized sample comprised 1094 patients al-
located 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 gen-
erally 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.
Long-Term Analyses
The long-term sample comprised 346 patients who rolled
over from the short-term studies, of whom 170 (49.1%) had hos-
tility at baseline of the short-term studies (P7 score ≥3).
Efficacy
PANSS-EC Score Change in the Efficacy Sample
Short-Term Analyses
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

TABLE 1. Patient Disposition, Reasons for Discontinuation, and Baseline Demographic and Clinical Characteristics Stratified by
Baseline Hostility (Randomized Sample)

With Hostility (P7 Score ≥3) Without Hostility (P7 Score <3)
Brexpiprazole Brexpiprazole Brexpiprazole Brexpiprazole
Short-Term Studies Placebo 2 mg 4 mg Placebo 2 mg 4 mg
Patient disposition, n (%)
Randomized 186 172 198 180 194 164
Completed 117 (62.9) 119 (69.2) 130 (65.7) 108 (60.0) 133 (68.6) 119 (72.6)
Discontinued 69 (37.1) 53 (30.8) 68 (34.3) 72 (40.0) 61 (31.4) 45 (27.4)
Patient withdrew consent 21 (11.3) 16 (9.3) 31 (15.7) 21 (11.7) 32 (16.5) 23 (14.0)
Lack of efficacy 16 (8.6) 21 (12.2) 18 (9.1) 23 (12.8) 16 (8.2) 5 (3.0)
Adverse event 26 (14.0) 15 (8.7) 16 (8.1) 28 (15.6) 11 (5.7) 14 (8.5)
Other 6 (3.2) 1 (0.6) 3 (1.5) 0 (0.0) 2 (1.0) 3 (1.8)
Efficacy sample 180 (96.8) 170 (98.8) 196 (99.0) 178 (98.9) 189 (97.4) 163 (99.4)
Safety sample 186 (100.0) 172 (100.0) 198 (100.0) 180 (100.0) 194 (100.0) 164 (100.0)
Demographic characteristics
Age, mean (SD), y 38.5 (11.2) 38.3 (10.1) 39.7 (10.8) 40.6 (10.1) 38.2 (11.1) 39.7 (11.5)
BMI, mean (SD), kg/m2 26.6 (5.9) 26.8 (5.7) 27.5 (6.3) 26.5 (5.1) 26.6 (5.8) 26.7 (6.1)
Male, n (%) 114 (61.3) 107 (62.2) 121 (61.1) 114 (63.3) 125 (64.4) 103 (62.8)
Race, n (%)
White 110 (59.1) 104 (60.5) 114 (57.6) 120 (66.7) 133 (68.6) 107 (65.2)
Black/African American 49 (26.3) 46 (26.7) 62 (31.3) 40 (22.2) 37 (19.1) 30 (18.3)
Asian 16 (8.6) 12 (7.0) 13 (6.6) 10 (5.6) 14 (7.2) 15 (9.1)
Other 11 (5.9) 10 (5.8) 9 (4.5) 10 (5.6) 10 (5.2) 12 (7.3)
Clinical characteristics
Age at first diagnosis, mean (SD), y 25.8 (8.7) 25.9 (8.2) 26.4 (8.1) 27.2 (9.8) 26.0 (8.0) 27.2 (9.1)
Duration of current episode, mean (SD), wk 2.3 (1.9) 2.6 (2.1) 2.3 (1.7) 3.1 (3.4) 2.9 (3.1) 2.4 (2.2)
PANSS total score, mean (SD) 99.1 (11.8) 100.4 (13.1) 98.6 (10.6) 91.4 (11.5) 92.2 (12.2) 90.7 (12.9)
CGI-S score, mean (SD) 4.9 (0.6) 5.0 (0.6) 4.9 (0.6) 4.8 (0.6) 4.9 (0.6) 4.7 (0.6)
BMI indicates body mass index; CGI-S, Clinical Global Impressions — Severity of illness.

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. www.psychopharmacology.com 3

Citrome et al Journal of Clinical Psychopharmacology • Volume 39, Number 6, November/December 2019

FIGURE 1. Mean change in PANSS-EC score from baseline to (A) week 6 and (B) open-label week 52 in the efficacy sample, and to (C) week 6
and (D) open-label week 52 among patients with hostility at baseline (P7 score ≥3). *P < 0.05, **P < 0.01, ***P < 0.001 versus placebo;
pooled analysis; MMRM (short-term); observed cases (long-term). Mean (SD) PANSS-EC scores at baseline: (A) placebo, 12.6 (3.8);
brexpiprazole 2 mg, 12.8 (3.8); brexpiprazole 4 mg, 12.9 (3.7); (B) 12.7 (3.5); (C) placebo, 15.3 (2.9); brexpiprazole 2 mg, 15.4 (3.2);
brexpiprazole 4 mg, 15.0 (3.1); and (D) 15.1 (2.9). OL indicates open label.

(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).
Long-Term Analyses
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 im-
provement occurred during the first 6 to 10 weeks of treatment,
and the benefits were maintained over 58 weeks (Fig. 1B).
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).
Long-Term Analyses
The mean change in PANSS-EC score from baseline to open-
label week 52 in patients with hostility at baseline (P7 score ≥3) is pre-
sented 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).

PANSS-EC Score Change in Patients With Hostility at
Baseline (P7 Score ≥3)
Short-Term Analyses
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
P7 (Hostility) Score Change in Patients With Hostility at
Baseline (P7 Score ≥3)
Short-Term Analyses
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,

4 www.psychopharmacology.com © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

Journal of Clinical Psychopharmacology • Volume 39, Number 6, November/December 2019 Brexpiprazole's Effect on Agitation

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).
Supportive Analyses
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 Supple-
mental Digital Content 1, http://links.lww.com/JCP/A614, and
Supplementary Figures 1 and 2, Supplemental Digital Contents
2 and 3, http://links.lww.com/JCP/A615 and http://links.lww.
com/JCP/A616, for details).

Safety and Tolerability

FIGURE 2. The LS mean change in PANSS hostility item (P7) score
from baseline to week 6 among patients with hostility at baseline
(P7 score ≥3). *P < 0.05, **P < 0.01 versus placebo; pooled analysis;
MMRM. Mean (SD) P7 scores at baseline: placebo, 3.4 (0.6);
brexpiprazole 2 mg, 3.4 (0.7); and brexpiprazole 4 mg, 3.4 (0.6).
−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 ob-
served 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).
Long-Term Analyses
With long-term brexpiprazole treatment, patients with hostility
at baseline showed further improvement in P7 score, changing from
TEAEs in Patients With/Without Hostility at Baseline
(P7 Score ≥3)
Short-Term Analyses
In patients with hostility at baseline, the proportion of pa-
tients 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 base-
line 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 dis-
ease) was more common in the placebo subgroups than in the
brexpiprazole subgroups (Table 2).
Supportive Analyses
In patients with a P7 score of 2 or greater at baseline, a sim-
ilar pattern of TEAEs was observed (see Supplemental Digital
Content 1, http://links.lww.com/JCP/A614, and Supplementary
Table 1, Supplemental Digital Content 4 http://links.lww.com/
JCP/A617, for details).

TABLE 2. Treatment-Emergent Adverse Events Stratified by Baseline Hostility (Safety Sample)

With Hostility (P7 Score ≥3) Without Hostility (P7 Score <3)
Placebo Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo Brexpiprazole 2 mg Brexpiprazole 4 mg
Short-Term Studies, n (%) (n = 186) (n = 172) (n = 198) (n = 180) (n = 194) (n = 164)
At least 1 TEAE 104 (55.9) 105 (61.0) 119 (60.1) 110 (61.1) 105 (54.1) 98 (59.8)
TEAEs occurring in ≥5% of patients in any brexpiprazole group
Headache 20 (10.8) 20 (11.6) 23 (11.6) 22 (12.2) 16 (8.2) 18 (11.0)
Insomnia 23 (12.4) 20 (11.6) 19 (9.6) 21 (11.7) 21 (10.8) 23 (14.0)
Akathisia 11 (5.9) 9 (5.2) 17 (8.6) 6 (3.3) 8 (4.1) 8 (4.9)
Agitation 17 (9.1) 7 (4.1) 14 (7.1) 15 (8.3) 20 (10.3) 12 (7.3)
Weight increased 5 (2.7) 7 (4.1) 13 (6.6) 1 (0.6) 5 (2.6) 3 (1.8)
Schizophrenia 17 (9.1) 8 (4.7) 11 (5.6) 21 (11.7) 9 (4.6) 10 (6.1)
Constipation 8 (4.3) 8 (4.7) 10 (5.1) 8 (4.4) 7 (3.6) 5 (3.0)
Nausea 6 (3.2) 11 (6.4) 2 (1.0) 7 (3.9) 5 (2.6) 5 (3.0)

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. www.psychopharmacology.com 5

Citrome et al Journal of Clinical Psychopharmacology • Volume 39, Number 6, November/December 2019
DISCUSSION
In this sample of patients hospitalized with an acute exac-
erbation 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 fur-
ther 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 fur-
ther studied as a potential treatment option for patients with ag-
itation 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 influ-
ence agitation and hostility outcomes. An analysis of acute schizo-
phrenia 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 se-
dation 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 pres-
ent analysis among patients with hostility. Rates of akathisia as a
TEAE over 6 weeks were slightly higher among patients with hos-
tility 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 explor-
atory 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
6 www.psychopharmacology.com
antipsychotic cannot be made. Patients were not specifically se-
lected 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 po-
tential 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 poten-
tial to be an efficacious and well-tolerated treatment for agitation
and hostility in schizophrenia.
ACKNOWLEDGMENTS
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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www.psychopharmacology.com 7
Supplementary Content 1. Results of supportive analyses in patients with a P7 cut-off
of ≥2 points (at least ‘minimal’ hostility)

PANSS-EC score change in patients with hostility at baseline (P7 score ≥2)

Short-term analyses: In patients with P7 score ≥2 at baseline, brexpiprazole 4 mg

(LSMD: -1.34 [95% CLs: -2.14, -0.55]; p=0.0010), but not brexpiprazole 2 mg (-0.76
[-1.57, 0.05]; p=0.065), was superior to placebo in reducing the PANSS-EC score at
Week 6 (Supplementary Figure 1a).
Long-term analyses: Patients with P7 score ≥2 at baseline showed further improvement
in PANSS-EC score with long-term brexpiprazole treatment, changing from baseline by a
mean (SD) of -6.6 (3.8) points to open-label Week 26 (n=134), and by -7.2 (3.6) points
to open-label Week 52 (n=99) (Supplementary Figure 1b).

P7 (hostility) score change in patients with hostility at baseline (P7 score ≥2)
Short-term analyses: In patients with P7 score ≥2 at baseline, brexpiprazole 4 mg was
superior to placebo in reducing P7 score at Week 6 (LSMD: -0.34 [95% CLs: -0.55,
-0.12]; p=0.0024), independent of improvement in positive symptoms (MMRM Model 1)
(Supplementary Figure 2). Similar benefits were observed for brexpiprazole 4 mg when
also adjusting for akathisia (MMRM Model 2: -0.32 [-0.54, -0.11]; p=0.0034), or
akathisia and somnolence (MMRM Model 3: -0.33 [-0.54, -0.11]; p=0.0033).
Brexpiprazole 2 mg showed numerical advantages over placebo in these models (MMRM
Model 1: -0.14 [-0.36, 0.08]; p=0.22; MMRM Model 2: -0.12 [-0.34, 0.10]; p=0.28;
MMRM Model 3: -0.12 [-0.34, 0.10]; p=0.28).

Long-term analyses: Patients with P7 score ≥2 at baseline showed further improvement

in P7 score with long-term brexpiprazole treatment, changing from baseline by a mean
(SD) of -1.6 (1.1) points to open-label Week 26 (n=134), and by -1.7 (1.1) points to
open-label Week 52 (n=99).

TEAEs in patients with/without hostility at baseline (P7 score ≥2)

Short-term analyses: In patients with P7 score ≥2 at baseline, the incidence of TEAEs
over 6 weeks was comparable across treatment groups, in the range of 58.4–60.1%
(Supplementary Table 1). A similar incidence of TEAEs was seen in patients with P7 score
<2 at baseline, except in the brexpiprazole 2 mg group, which had a lower incidence of
TEAEs (53.3%).

The incidence of akathisia over 6 weeks was higher among patients with P7 score ≥2
than those with score <2 (Supplementary Table 1). The highest incidence of akathisia
was among patients with hostility at baseline who received the brexpiprazole 4 mg dose
(8.1%). The incidences of sedation and somnolence were low (each <5%) in all
treatment groups, regardless of hostility status.

Supplement to: Effect of brexpiprazole on agitation and hostility in patients with

schizophrenia: post hoc analysis of short- and long-term studies
 Supplementary Figure 1. Mean change in PANSS-EC score from baseline to (a) Week 6
and (b) open-label Week 52 among patients with hostility at baseline (P7 score ≥2)

a) 0 b) 1
0
-1
LS mean (SE) change from baseline

-1 -2

Mean (SD) change from baseline

* -3
**
-4
-2
-5
**
-6

*** -7
-3
-8
**
-9
*** -10
-4 Placebo (n=251)
*** -11
Brexpiprazole 2 mg (n=256)
-12
Brexpiprazole 4 mg (n=268) Brexpiprazole 2–4 mg (n=246)
-5 -13
0 1 2 3 4 5 6 0 2 4 6 810
OL412141618202224262830
OL14 323436384042
OL26 44464850525456
OL38 58
OL52
Week Week

*p<0.05, **p<0.01, ***p≤0.001 versus placebo; pooled analysis; mixed model repeated measures (short-term); observed cases
(long-term).

Mean (SD) PANSS-EC scores at baseline: (a) placebo, 14.2 (3.2); brexpiprazole 2 mg, 14.2 (3.4); brexpiprazole 4 mg,
14.1 (3.3); (b) 14.1 (3.1).

EC, Excited Component; LS, least squares; OL, open-label; P7, PANSS hostility item; PANSS, Positive and Negative
Syndrome Scale; SD, standard deviation; SE, standard error.

Supplement to: Effect of brexpiprazole on agitation and hostility in patients with

schizophrenia: post hoc analysis of short- and long-term studies
Supplementary Figure 2. LS mean change in PANSS hostility item (P7) score from
baseline to Week 6 among patients with hostility at baseline (P7 score ≥2)

Analysis 3
Analysis 2 (adjusted for
Analysis 1 (adjusted for positive symptoms,
(adjusted for positive symptoms akathisia, and
positive symptoms) and akathisia) somnolence)
0.0
LS mean (SE) change from baseline

-0.2

-0.4

-0.6

-0.8

** ** **
-1.0
Placebo (n=251)
Brexpiprazole 2 mg (n=256)
Brexpiprazole 4 mg (n=268)

**p<0.01 versus placebo; pooled analysis; mixed model repeated measures.

Mean (SD) P7 scores at baseline: placebo, 3.0 (0.8); brexpiprazole 2 mg, 3.0 (0.9); brexpiprazole 4 mg, 3.0 (0.8).

LS, least squares; P7, PANSS hostility item; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; SE,
standard error.

Supplement to: Effect of brexpiprazole on agitation and hostility in patients with

schizophrenia: post hoc analysis of short- and long-term studies
Supplementary Table 1. Treatment-emergent adverse events stratified by baseline
hostility (safety sample)

Short-term studies, With hostility (P7 score ≥2) Without hostility (P7 score <2)
n (%)
Placebo Brexpiprazole Brexpiprazole Placebo Brexpiprazole Brexpiprazole
(n=257) 2 mg 4 mg (n=109) 2 mg 4 mg
(n=261) (n=271) (n=105) (n=91)

At least one TEAE 150 (58.4) 154 (59.0) 163 (60.1) 64 (58.7) 56 (53.3) 54 (59.3)

TEAEs occurring in ≥5% of patients in any brexpiprazole group

Headache 30 (11.7) 25 (9.6) 33 (12.2) 12 (11.0) 11 (10.5) 8 (8.8)

Insomnia 31 (12.1) 29 (11.1) 26 (9.6) 13 (11.9) 12 (11.4) 16 (17.6)

Akathisia 13 (5.1) 13 (5.0) 22 (8.1) 4 (3.7) 4 (3.8) 3 (3.3)

Agitation 21 (8.2) 16 (6.1) 20 (7.4) 11 (10.1) 11 (10.5) 6 (6.6)

Schizophrenia 25 (9.7) 16 (6.1) 15 (5.5) 13 (11.9) 1 (1.0) 6 (6.6)

Weight increased 5 (1.9) 9 (3.4) 15 (5.5) 1 (0.9) 3 (2.9) 1 (1.1)

Nausea 8 (3.1) 13 (5.0) 5 (1.8) 5 (4.6) 3 (2.9) 2 (2.2)

P7, Positive and Negative Syndrome Scale hostility item; TEAE, treatment-emergent adverse event.

Supplement to: Effect of brexpiprazole on agitation and hostility in patients with

schizophrenia: post hoc analysis of short- and long-term studies