Article

Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder

Bipolar Disorder Research Program, UT Southwestern Medical Center, Dallas, Texas 75390-9121, USA.
Journal of Affective Disorders (Impact Factor: 3.38). 05/2008; 107(1-3):145-54. DOI: 10.1016/j.jad.2007.08.015
Source: PubMed

ABSTRACT

This analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations of patients with acute manic or mixed episodes of bipolar I disorder.
Acutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two randomized, three-week, flexible-dose, double-blind, placebo-controlled trials (N=516) and stratified by disease severity (Young Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed.
Aripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or non-rapid cycling (p<0.01 for each subpopulation); in men and women (p=0.001 for both); in patients in the 18-40 and 41-55 year age groups (p<or=0.001 for both); and in three subgroups stratified by baseline severity of depressive symptoms using the Montgomery-Asberg Depression Rating Scale (p<0.05). The treatment-emergent adverse events reported in >or=5% of patients aged 18-40 years receiving aripiprazole were similar to those reported for the overall population.
This post hoc analysis utilized pooled data from two short-term studies.
Efficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.

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Research report
Efficacy and safety of aripiprazole in subpopulations with acute
manic or mixed episodes of bipolar I disorder
Trisha Suppes
a,
, James Eudicone
b
, Robert McQuade
c
,
Andrei Pikalov III
c
, Berit Carlson
b
a
Director, Bipolar Disorder Research Program, UT Southwestern Medical Center, Dallas, Texas, USA
b
Bristol-Myers Squibb America Pharmaceuticals, Inc., USA
c
Otsuka America Pharmaceuticals, Inc., USA
Received 19 January 2007; received in revised form 17 August 2007; accepted 22 August 2007
Abstract
Background: This analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations
of patients with acute manic or mixed episodes of bipolar I disorder.
Methods: Acutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two
randomized, three-week, flexible-dose, double-blind, placebo-controlled trials ( N =516) and stratified by disease severity (Young
Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline
severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed.
Results: Aripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more
severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or non-
rapid cycling (p b 0.01 for each subpopulation); in men and women (p =0.001 for both); in patients in the 1840 and 4155 year
age groups (p 0.001 for both); and in three subgroups stratified by baseline severity of depressive symptoms using the
Montgomery-Åsberg Depression Rating Scale (p b 0.05). The treatment-emergent adverse events reported in 5% of patients aged
1840 years receiving aripiprazole were similar to those reported for the overall population.
Limitations: This post hoc analysis utilized pooled data from two short-term studies.
Conclusion: Efficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often
associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Acute mixed or manic episodes; Aripiprazole; Bipolar I disorder
1. Introduction
Bipolar I disorder is associated with signific ant
morbidity, mortality, and reduced quality of life (Bauer
and Pfenning, 2005; Hirschfeld et al., 2003; Kupfer et al.,
2002). In the United States, bipolar I and II disorders
Journal of Affective Disorders xx (2007) xxx xxx
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Corresponding author. Department of Psychiatry, UT Southwest-
ern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, USA 75390-
9121. Tel.: +1 214 648 6925; fax: +1 214 648 6922.
E-mail address: trisha.suppes@utsouthwestern.edu (T. Suppes).
0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2007.08.015
ARTICLE IN PRESS
Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
disorder, J. Affect. Disord. (2007), doi:10.1016/j.jad.2007.08.015
Page 1
have a combined estimated lifetime prevalence of 3.9%
(Kessler et al., 2005).
The majority of patients with bipolar disorder are in
the depressive phase of the illness when they present to
the physician (Post, 2005). Although comparatively
short in duration, the manic phase is unsettling and can
be devastating to both the patient and family and can lead
to hospital ization if severe enough. An ideal therapy for
bipolar disorder should have a broad range of efficacy,
rapid onset of action, and an established history of safety
and tolerability.
Several classes of medications have completed
placebo-controlled trials and are approved for the
treatment of mania associated with bipolar I disorder,
including lithium, anticonvulsants, and second-genera-
tion antipsychotics. However, there have been few
studies that have examined the efficacy and safety of
second-generation antipsychotics in selected subpopula-
tions of patients with bipolar disorder, including patients
with acute manic episodes with or without psychotic
features (Baldessarini et al., 2003; Chengappa et al.,
2003; Adityanjee and Shultz, 2002), manic or mixed
episodes (Baldessarini et al., 2003; Chengappa et al.,
2003), and rapidly cycling episodes (Suppes et al., 2005;
Vieta et al., 2004; Sanger et al., 2003).
The safety and efficacy of aripiprazole have been
evaluated in inpatients with bipolar I disorder who were
experiencing acute manic or mixed episodes. In two
flexible-dose, double-blind, placebo-controlled, three-
week studies, aripiprazole was associated with signifi-
cantly greater symptom improvement than placebo (Sachs
et al., 2006; Keck et al., 2003b). In a third three-week,
placebo-controlled, fixed-dose trial, the primary outcome
measurement in the aripiprazole-treated group was not
different from that in the placebo group due to a higher
than usual placebo response rate (data on file, April 2003).
This third trial was considered a negative trial. In a 12-
week, double-blind, comparative study of aripiprazole
and haloperidol in inpatients and outpatients, aripiprazole
demonstrated improvement of symptoms comparable
with haloperidol (mean change in Young Mania Rating
Scale [YMRS]), with a significantly greater rate of res-
ponse (defined as 50% decrease in YMRS scores and
continuation of therapy) and a higher completion rate than
haloperidol at end point (Vietaetal.,2005). Across these
studies, aripiprazole displayed a safety and tolerability
profile similar to that observed in the short-term studies of
patients with schizophrenia and schizoaffective disorder.
The objective of the following post hoc analyses was
to examine the efficacy, safety, and tolerability of
aripiprazole in various subpopulations of patients with
acute manic or mixed episodes of bipolar I disorder.
2. Methods
The data were pooled from two three-week, random-
ized, double-blind, p lacebo- controlled, multicenter,
pivotal, flexible-dose clinical trials in order to achieve
a large sample of patients for subpopulation analyses
(Sachs et al., 2006; Keck et al., 2003b). The data from
the third fixed-dose study were n ot included in these
analyses because of the differences in study design
compared with the flexible-dose trials. The designs of
the two flexible-dose studies were similar, and details of
the study design and population can be found in the
respective studies (Sachs et al., 2006; Keck et al.,
2003b). Both studies were conducted in the United
States (29 centers in the study by Sachs et al. (2006), and
at 38 centers in the study by Keck et al. (2003b)).
In both trials, eligible patients were randomized to
either placebo or aripiprazole 30 mg/d after initial
screening of 17 days. The dose of medication could be
reduced to 15 mg/d for tolerability, if needed. All
patients were hospitalized for at least the first two weeks
of the studies but could be discharged afterwards if their
Clinical Global Impression-Bipolar Version (CGI-BP)
Severity of Illness (mania) score was 3 (mildly ill,
minimally ill, or not ill) and they had a CGI-BP
improvement from baseline (mania) score 2 (much
improved or very much improved). Patients who did not
meet these criteria remained in the hospital for the last
week of treatment. In the first study (Keck et al., 2003b),
patients who did not respond by the end of week 2
(defined as change from preceding phase [mania] score
of 4 [no improvement] to 7 [very much worse]) were
discontinued from double-blind therapy and offered
open-label aripiprazole treatment for week 3. Concom-
itant use of psychotropic medications (apart from study
medication) was prohibited during the study (including
the screening phase) except for lorazepam. Lorazepam
treatment was allowed only on days 14( 6 mg/d), 5
7( 4 mg/d), and 810 ( 2 mg/d) (Sachs et al., 2006;
Keck et al., 2003b).
From these pooled studies, three datasets were uti-
lized in this analysis. First, the randomized patient
population, which included all patients randomized to
study medication (aripiprazole, n = 268; placebo,
n = 266), was used to calculate those patients who com-
pleted the study. Second, the efficacy population
(efficacy sample), which included all patients random-
ized to study medication who received a baseline evalu-
ation of efficacy and at least one efficacy assessment
after initiation of drug (aripiprazole, n = 261; placebo,
n = 255), was used to calculate all efficacy assessments.
Finally, the safety population, those patients who had
2 T. Suppes et al. / Journal of Affective Disorders xx (2007) xxxxxx
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Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
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Page 2
received at least one dose of study medication (aripipra-
zole, n = 263; placebo, n =260), was used to calculate
adverse-event rates.
The 516 patients of the efficacy sample had DSM-IV
diagnoses of acute manic or mixed episodes of bipolar I
disorder and were pooled from the two flexible-dose
studies: CN138-009 and CN138-074 (Sachs et al., 2006;
Keck et al., 2003b). These patients were stratified into
different subpopulations based on the following char-
acteristics: 1) severity of mania (YMRS N median 27 and
YMRS median 27); 2) manic or mixed episode (based
on DSM-IV and Structured Clinical Interview for DSM-
III-R [SCID] definitions); 3) with or without psychotic
symptoms (psychosis defined as Positive and Negative
Syndrome Scale [PANSS] total score 60 and a score
of 4 on at least two of the following items: PANSS
positive items 1 [delusion], 2 [conceptual organization],
3 [hallucinatory behavior], and 6 [suspiciousness/
persecution]); 4) rapid cycling vs. non-rapid cycling
episodes (as defined by DSM-IV: at least four episodes
of a mood disturbance in the previous 12 months that
met criteria for a major depressive, manic, mixed, or
hypomanic episode); 5) gender; and 6) age was stratified
based on relatively early in course of illness (18
40 years), mid course with a likely history of more
episodes (4155 years), and later course of illness
(N 55 years).
The primary efficacy outcome measure for these post
hoc analyses was the mean change from baseline to week
3 (study end point) in YMRS total scores, using the last
observation carried forward (LOCF) methodology.
Efficacy parameters were analyzed using ANCOVA
with baseline score as a covariate, including terms for
treatment and study. In addition, another analysis was
performed to further define mixed or manic populations
using baseline Montgomery-Åsberg Depression Rating
Scale (MADRS) score criteria (MADRS 8 [more pure
manic], 918 [in te rme di at e], and N 18 [mor e p ure
mixed]). A mixed-model repeated measures analysis of
variance was performed on efficacy data from these
MADRS subgroups in order to evaluate the time course
of improvement in bipolar I disorder. The analysis was
performed on an intent-to-treat basis utilizing observed
cases data, which included patients with a baseline
assessment and at least one post-baseline measurement.
A mixed-model repeated measures analysis of variance
was fitted for change from baseline in YMRS total score.
Baseline YMRS total scores, protocol, treatment, and
time-treatment interaction were included in the model as
fixed effects. Intercept and time were included as random
effects uti lizi ng an unstructured covariance matrix.
Contrasts w ere used within the repeated measures
model to assess the change from baseline to each time
point between treatment groups. Additionally, a natural
log transformation was applied to the weekly time points
measured from baseline to give a more nearly linear
relationship of change from baseline in total YMRS
score.
Finally, analyses were performed comparing percen-
tages of responders (defined as subjects with 50%
reduction in YMRS score from baseline) and remitters
(defined as having YMRS 12) at week 3 end point
(LOCF) in aripiprazole vs. placebo treatment groups in all
subpopulations examined (age, gender, current episode
manic or mixed, absence or presence of psychosis, absence
or presence of rapid cycling, and baseline MADRS score).
The incidence of treatment-emergent adverse events
(TEAEs) occurring in 5% of patients on aripiprazole
or placebo and that wer e at least twice the rate of the
placebo was assessed.
3. Results
3.1. Patient demographics, baseline characteristics, pa-
tient disposition, and dose
The overall disposition of the randomized population
from the pooled studies is shown in Table 1. Of the 516
patients included in the efficacy sample, 255 received
placebo and 261 received aripiprazole. Baseline char-
acteristics were comparable between the two treatment
groups (Table 2). At end point, the mean aripiprazole
dose was 27.8 mg/d± 5.4 mg/d in the total population,
Table 1
Disposition of randomized sample from two pooled three-week studies
Aripiprazole Placebo
Reasons for discontinuation N (%) N (%)
Randomized 268 266
Completed study 129 (48%) 98 (37%)
Discontinued due to
adverse events
a
26 (10%) 23 (9%)
Lack of efficacy
b
42 (16%) 81 (30%)
Withdrew consent 63 (24%) 54 (20%)
Lost to follow-up 2 (1%) 2 (1%)
Other 6 (2%) 8 (3%)
a
The most frequent adverse events ( 1%) that led to study
discontinuation in the aripiprazole group were agitation, akathisia,
anxiety, insomnia, manic reaction; in the placebo group, they were
agitation, personality disorder, and manic depressive reaction.
b
Includes patients from one trial not responding at week 2 (as indicated
by Clinical Global Impression-Bipolar Version score change from
preceding phase [mania] score of 47); these patients were offered
open-label aripiprazole treatment.
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Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
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Page 3
with 85% of patients receiving the maximum dose of
30 mg/d. There were no clinically meaningful differ-
ences in the end point doses (range, mean± SE: 26.8 ±
0.3 mg/d to 28.7±0.4 mg/d) of aripiprazole within the
analyzed subpopulations.
3.2. Efficacy
3.2.1. Baseline severity of disease
Patients were divided into two groups based on their
median baseline YMRS total score. A baseline YMRS
score of 27 corresponded to less severe illness, while a
score N 27 reflected more severe symptoms. Mean
baseline± SE YMRS scores in either severity group
were similar between the treatment arms (YMRS 27:
placebo, 24.5± 0.2; aripiprazole, 24.0 ±0.2; p =NS;
YMRS N 27: placebo, 33.1 ±0.4; aripiprazole, 33.1 ±
0.4; p = NS). Patients on aripiprazole in both groups
demonstrated a significant improvement in mean YMRS
total scores at end point compared with placebo (mean
change ±SE: 9. 6±0.9 vs. 5.7 ± 0. 9, r espectively,
p b 0.01 for baseline YMRS 27; and 11.9± 1.1 vs.
5.3 ±1.1, respectively, p b 0.001 for basel ine YMRS
N 27).
3.2.2. Type of episode: manic vs. mixed
Patients were stratified into groups experiencing manic
or mixed index episodes at baseline, as defined by the
DSM-IVand the SCID. The initial efficacy of aripiprazole
compared with placebo was evident as early as day 4 in
both manic (p= 0.001) and mixed (pb 0.01) groups (data
not shown). At end point, aripiprazole demonstrated a
significant improvement in mean YMRS total scores
compared with placebo (mean change±SE): 10.2±0.9
vs. 4.7± 0.9, respectively, p b 0.001 for t he manic
subpopulation of patients; and 11.7± 1.1 vs. 7.0±1.0,
respectively, pb 0.01 for the mixed subpopulation of
patients (Fig. 1a).
3.2.3. Absence or presence of psychotic symptoms
Aripiprazole-treated patients, both with and without
baseline psychotic symptoms, demonstrated significant-
ly improved YMRS total scores at end point compared
with those treated with placebo (mean change± SE):
1 2.2 ± 2.0 vs. 5.0 ±1.8, respe ctively, p b 0.0 1, f or
patients with psychotic symptoms; and 10.5± 0.7 vs.
5.9 ±0.8, respectively, p b 0.001, for patients without
psychotic symptoms (Fig. 1b).
3.2.4. Frequency of episode: rapid cycling vs. non-
rapid cycling
The mean change from baseline to end point in mean
YMRS total scores was significantly greater in aripi-
prazole-treated patients compared with placebo-treated
patients in both the rapid cycling (mean change± SE:
10.9± 1.4 vs. 5.0± 1.4, respectively, p b 0.01) and
non-rapid cycling (mean change ± SE: 10.7 ±0.8 vs.
5.7 ±0.8, respectively, p b 0.001) groups (Fig. 1 c).
3.2.5. Gender
There were n o statistically significant differences in
the baseline YMRS scores in either male or female
patients between the aripiprazole- and placebo-treated
groups (male group: aripiprazole, n = 123; mean ±SE:
28.3± 0.5 vs. placebo, n =115; 29.3± 0.5; female group:
aripiprazole, n =137; 28.7± 0.5 vs. placebo, n = 140;
28.5± 0.5). When compared with placebo, aripiprazole
significantly reduced YMRS scores at end point
regardless of gender. In male patients, changes in
YMRS total scores from baseline in aripiprazole vs.
placebo groups were (mean±SE): 10.8± 1.0 vs. 5.3 ±
1.0; p = 0.001. Similar results were observed in female
patients (mean± SE): aripiprazole, 10.7 ±1.0 vs. pla-
cebo, 5.7 ±1.0; p =0.001.
Table 2
Patient demographics and baseline characteristics of efficacy sample
a
Aripiprazole Placebo
Parameter (n = 261) (n = 255)
Age (y), mean± SD 38.9± 11.9 40.3± 11.0
Gender, n (%)
Male 123 (47) 115 (45)
Female 138 (53) 140 (55)
Race, n (%)
White 197 (75) 186 (73)
Black 41 (16) 49 (19)
Hispanic 11 (4) 14 (5)
Other 12 (5) 6 (2)
Current episode, n (%)
Manic 168 (64) 158 (62)
Mixed 93 (36) 97 (38)
Rapid cycling, n (%)
No 209 (80) 204 (80)
Yes 52 (20) 51 (20)
Psychotic symptoms, n (%)
No 221 (83) 201 (79)
Yes 45 (17) 54 (21)
Baseline YMRS total score (n =259) (n=254)
mean±SD
b
28.5± 5.6 28.8 ± 5.8
Baseline MADRS total score (n = 259) (n = 254)
mean±SD
b
14.5± 7.6 15.2 ± 8.5
YMRS=Young Mania Rating Scale; MADRS = Montgomery-Åsberg
Depression Rating Scale.
a
Efficacy data set: all patients receiving a baseline and at least one post-
baseline assessment of efficacy.
b
Includes patients who provided post-baseline YMRS data.
4 T. Suppes et al. / Journal of Affective Disorders xx (2007) xxxxxx
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Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
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Page 4
Female patients had a higher incidence of rapid
cycling (72/277, 26%) compared with the male patients
(n = 31/239, 13%; p = 0.0003). The propor tion of rapid
cyclers in the total patient population was 20% (103/
516). Baseline MADRS total scores were numerically
higher in female than in male patients, regardless of
study medication (mean baseline ±SE)men: aripipra-
zole, n = 123; 13.8 ±0.7 vs. placebo, n = 115; 14.1±0.7;
p = NS; women: aripiprazole, n = 137; 15.1± 0.6 vs.
placebo, n = 140; 16.0 ±0.7; p =NS). There were no
observed gender differences in baseline MADRS line
items with the exception of reduced appetite in female
patients (which was approximately two times higher
than in male patients; data not shown).
3.2.6. Age
Three age groups were examined: 1840 years
(aripiprazole, n = 146; placebo, n = 116), 4155 years
(aripiprazole, n =87; placebo, n =116), and N 55 years
(aripiprazole, n=27; pl ac ebo , n = 23). Baseline YMRS
scores were similar between aripiprazole and placebo
treatment groups within each age group ( p =NS).
Change fro m baseline to end point i n YMRS scores
in aripiprazole-treated vs. placebo-treated patients were
(mean± SE): 10.6±0.9 vs. 5. 7 ±1. 0, in the 1840
age group ( p b 0.01) and 11.7± 1.2 vs. 5.5 ±1.0, in
the 4155 age group (p =0.001). In the N 55 age group
there was no statistical difference between treatment
groups (mean± SE): aripiprazole, 8.7 ±2.2 and place-
bo, 5.1 ± 2.3 (p =NS).
3.2.7. Level of depressive symptoms at baseline based
on MADRS
To further evaluate patient subpopulations as manic
and mixed, patients were divided by baseline MADRS
score into a more purely mixed group (baseline MADRS
N 18), more purely manic group (baseline MADRS 8),
and an intermediate mixed group (MADRS 918).
Since the baseline MADRS scores (mean ±SD) for
SCID-defined mixed population were 18.5 ±0.75 (ari-
piprazole) and 19.5± 0.8 (placebo), the intermediate and
high MADRS-d efined subpopulations would be repre-
sentative of DSM-IV-defined mixed-episode pati ent
population in this study.
There were no statistically significant differences
in baseline YMRS scores between aripiprazo le and
placebo treatment groups in any of the subgroups
analyzed (mea n ± SE): MADRS 8 subgroup: aripipra-
zole, 28.7± 0.8 vs. placebo, 29.5± 0.8 (p = NS); MADRS
918 subgroup: aripiprazole, 28.0± 0.5 vs. placebo,
28.7± 0.5 ( p =NS); and MADRS N 18 subgroup:
aripiprazole, 29.0± 0.7 vs. placebo, 28.6± 0.6 (p = NS)
Fig. 1. Mean change in YMRS total scores from baseline to trial end point (21 days).
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Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
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Page 5
(Fig. 2a c). With the exception of day 4 in the subgroup
of patients with baseline MADRS score 8, aripipra-
zole was statistically significantly better than placebo in
reducing YMRS total scores at all time points examined
and regardless of baseline MADRS score (Fig. 2ac).
3.3. Responder rate and remitter analysis by
subpopulation
The percentages of responders and remitters for each
of six subpopulations (age, gender, current episode,
Table 3
Percent responders/remitters at week 3 end point (last observation carried forward) in subpopulations
Subpopulation Percent responders
a
Percent remitters
b
(n = placebo, aripiprazole) Aripiprazole Placebo p value
c
Aripiprazole Placebo p value
c
Age group 1840 y (n = 115, 146) 45.89 24.35 0.0004 40.41 24.35 0.0080
4155 y (n = 116, 86) 47.67 28.45 0.0076 45.35 25.86 0.0045
N 55 y (n = 23, 27) 48.15 17.39 0.0355 37.04 17.39 0.2060
Gender Male (n = 115, 122) 49.18 26.09 0.0003 42.62 23.48 0.0023
Female (n = 139, 137) 44.53 25.18 0.0010 40.88 25.18 0.0071
Current episode Manic (n = 158, 167) 42.51 23.42 0.0003 38.32 21.52 0.0011
Mixed (n = 96, 92) 54.35 29.17 0.0006 47.83 29.17 0.0107
Psychotic symptoms Present (n =54, 44) 38.64 16.67 0.0209 31.82 16.67 0.0962
Absent (n =200, 215) 48.37 28.00 b0.0001 43.72 26.50 0.0003
Rapid cycling Present (n = 51, 52) 50.00 19.61 0.0018 48.08 21.57 0.0070
Absent (n =203, 207) 45.89 27.09 b0.0001 40.10 25.12 0.0015
Baseline MADRS MADRS 8(n=59, 64) 56.25 33.90 0.0183 45.31 30.51 0.0989
MADRS 918 (n =112, 123) 44.72 24.11 0.0010 43.90 23.21 0.0009
MADRS N 18 (n =83, 72) 41.67 21.69 0.0090 34.72 21.69 0.0756
YMRS=Young Mania Rating Scale.
a
Responder=end point YMRS total score 50% decrease from baseline.
b
Remitter= end point YMRS total score 12.
c
p value= two-sided Fisher's exact test.
Fig. 2. Mean change from baseline in YMRS total score.
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Page 6
psychotic sym ptoms, rapid cycling, and base line
MADRS) were higher overall in the aripiprazole-treated
group compared with the placebo-treated group and are
shown in Table 3. Both responder and remitter rates were
statistically significantly greater in patients receiving
aripiprazole regardless of whether patients were male or
female, the current episode was manic or mixed, with or
without rapid cycling, in age groups 1840 years or 41
55 years, and with baseline MADRS scores between
9 and 18 (please see Table 3 for all corresponding
p values).
3.4. Safety and tolerability
3.4.1. Treatment-emergent adverse events
In the overall population, the most common TEAEs
in the aripiprazole group (total n =263) that occurred at
5% and were at least twice the rate of the placebo
group (total n =260) were somnolence (aripiprazole,
20.9% vs. placebo, 8.1%), dyspepsia (aripiprazole,
18.6% vs. placebo, 9.2%), akathisia ( aripiprazole,
14.4% vs. placebo, 5 .0%), an d acc idental injury
(aripiprazole, 8.7% vs. placebo, 1.9%).
Stratification of patients by gender showed some
differences in the TEAE profile. For example, more than
twice as many male patients on aripiprazole (n=125)
compared with patients on placebo (n= 115) experienced
somnolence (23.2% vs. 6.1%), akathisia (9.6% vs. 3.5%),
pain extremity (8.8% vs. 2.6%), and rash (6.4% vs. 2.6%).
Akathisia (9.6%) was below the levels reported for
the aripiprazole group in the total population (14.4%).
More than twice as many female patients on aripiprazole
(n= 138) compared with patients on placebo (n=145)
experienced dyspepsia (18.8% vs. 9.0%), akathisia
(18.8% vs. 6.2%), constipation (17.4% vs. 6.2%),
vomiting (15.2% vs. 7.6%), accidental injury (9.4% vs.
0%), tremor (7.2% vs. 3.4%), increased salivation (7.2%
vs. 0%), and blurred vision (5.8% vs. 2.1%). Fewer male
patients experienced akathisia than did female patients in
the aripiprazole (male vs. female: 9.6% vs. 18.8%) and
placebo groups (male vs. female: 3.5% vs. 6.2%).
Stratification by age showed that in the 1840 age
group (aripiprazole, n = 148; placebo, n =118), the
TEAEs reported in 5% of patients that were at least
twice as high as placebo rates, overlapped with those
reported for the total population, and included somno-
lence (20. 9%), dys pepsia (1 9.6%), and akathisia
(18.2%). Additional TEAEs included nausea (24.3%),
constipation (11.5%), accidental injury (10.1%), dry
mouth (7.4%), tremor (7.4%), and back pain (5.4%). In
the 4155 age group (aripiprazole n =88, placebo
n = 116), somnolence (19.3%), dyspepsia (18.2%),
akathisia (12.5%), insomnia (8.0%), accidental injury
(8.0%), and increased salivation (6.8%) were reported at
least twice as frequently in the aripiprazole group than in
the placebo group. In the N 55 age group (aripiprazole,
n = 27, placebo, n = 26), somnolence (25.9%), nausea
(14.8%), infection (11.1%), anxiety (11.1%), increased
salivation (7.4%), gastroesophageal reflux (7.4%), and
nervousness (7.4%) were TEAEs reported in the
aripiprazole group that were at least twice the rate of
placebo. There were no patients N 55 years old reporting
akathisia in the aripiprazole group, while 11.5% of
patients in the placebo group reported akathisia.
4. Discussion
Previous studies have shown that patients with bipolar
disorder can present with a diverse range of symptoms
and conditions, and certain subpopulations are substan-
tially more refractory to pharmacologic treatment and
have poorer clinical and quality-of-life outcomes (Perlis
et al., 2006; Tondo et al., 2003), which makes planning
and implementation of appropriate treatment strategies
quite challenging. There is an unmet medical need to
elucidate effective treatment options for the mixed-
episode subpopulation of patients with bipolar I disorder
(Khanna et al., 2005; Weisler et al., 2004; Vieta, 2005;
Swann et al., 1997). To our knowledge, only olanzapine
and ziprasidone studies have shown equal efficacy in
patients with manic and mixed states (Baldessarini et al.,
2003; Keck et al., 2003a; Tohen et al., 2000; Tohen et al.,
1999).
In post hoc analysis of dysphoric mania vs. nondy-
sphoric mania, olanzapine was also shown to be sig-
nificantly more effective than placebo in the treatment of
patients with dysphoric mania (defined as Hamilton
Depression Rating, HAM-D N 20) (Baker et al., 2003). In
the present post hoc analysis, aripiprazole was effective
in reducing manic symptoms in patients with bipolar I
disorder regardless of baseline depressive symptoms (in
this study measured by MADRS baseline scores). The
significant effect of aripiprazole compared with placebo
was evident as early as day 4 in both the more pure mixed
(MADRS N 18) and intermediate (MADRS =918)
subpopulations. These data were consistent with the
findings of DSM-IV-defined manic and mixed-episode
patients displayed in Fig. 1a. To our knowledge, this
is the first study that examined the efficacy of an
antipsychotic in acutely manic patients stratified by
baseline MADRS scores in order to reflect patients that
would be defined as more purely manic, intermediate,
and more purely mixed with regard to their depressive
symptoms.
7T. Suppes et al. / Journal of Affective Disorders xx (2007) xxxxxx
ARTICLE IN PRESS
Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
disorder, J. Affect. Disord. (2007), doi:10.1016/j.jad.2007.08.015
Page 7
Second-generation antipsychotics are the most stud-
ied class of medications in bipolar patients with
psychosis, and the majority of evidence supports these
agents' efficacy. Consistent with the majority of
findings with second-generation antipsychotics (Khanna
et al., 2005; Hirschfeld et al., 2004; Baldessarini et al.,
2003; Adityanjee and Shultz, 2002; Tohen et al., 2000;
Tohen et al., 1999), the present post hoc analysis found
that aripiprazole was effective in the treatment of
patients regardless of their baseline level of psychosis.
Rapid cyclers constitute a substantial proportion of
patients with bipolar disorder (20% or higher), with the
majority of these patients being women (Schneck et al.,
2004; Yildiz and Sachs, 2004). Similar to other findings,
the majority (70%) of the rapid cycling subgroup in this
study were women. The proportions of women with a
history of rapid cycling were distributed equally in the
aripiprazole (53%) and placebo (55%) treatment arms.
This post hoc analysis found that the reduction in the
YMRS scores in either subpopulation group was signif-
icantly greater with aripiprazole than in the corresponding
placebo group. It should be noted, however, that longer-
term studies are needed to evaluate the sustained efficacy
of aripiprazole in rapid-vs. non-rapid cycling patients. Few
published studies have examined the use of second-
generation antipsychotics in patients with bipolar disorder
who have a history of rapid cycling. The most data are
available for olanzapine, which was shown to be effective
in the treatment of rapid cycling patients with bipolar I
disorder in short-term studies but less effective when
observed over a longer period (Suppes et al., 2005; Vieta
et al., 2004; Sanger et al., 2003; Tohen et al., 2000).
Younger patients (1855 years) treated with aripi-
prazole had signifi cantly better YMRS scores compared
with placebo, while patients N 55 years of age
demonstrated a less robust response with aripiprazole
treatment. It is possible that the number of patients in the
N 55 age group may not have been sufficient to detect
any significant differences between treatment arms.
There is currently a paucity of data on the treatment of
older patients with bipolar disorder, particularly in
double-blind c ontrolled tria ls. Howeve r, availa ble
reports for risperidone (Khanna et al., 2005; Hirschfeld
et al., 2004) and carbamazepine (Weisler et al., 2004,
2005) stated similar efficacy across the age groups
examined in these studies.
The results of the responder and remitter analyses
closely mirrored the individual analyses of efficacy in
subpopulations examined. Overall, aripiprazole-treated
patients had statistically significantly higher rates of
response and remission across subpopulations exam-
ined. The few exceptions where numerical difference
did not reach statistical significance in remitter analyses
were age group N 55, presence of psychotic symp toms,
and more purely manic (baseline MADRS 8) or more
purely depressive (MADRS N 18) patient groups.
Our results on the safety and tolerability of aripipra-
zole in the overall population are largely consistent with
previous individual study reports (Sachs et al., 2006;
Vieta et al., 2005; Keck et al., 2003b). In the younger age
group (1840 years), nausea (24.3%) and constipation
(11.5%) were more common than in the older age groups.
Interestingly, the older age group (N 55 years), which
would be predicted to be more susceptible to extrapyra-
midal symptom-related events, reported no aripiprazole-
associated akathisia. However, the sample size of this
subgroup was small relative to other age groups.
Notably, however, men had a lower percentage
of akathisia compared with women and the overall
populatio n. This finding is in contrast to recently
reported findings that showed that men with bipolar
disorder are potentially more susceptible to developing
akathisia (Ghaemi et al., 2006). In addition to akathisia,
constipation, vomiting, tremor, increased salivation, and
blurred vision were also more common in aripiprazole-
treated women than in men.
There are several limitations of this analysis. Pooled
post hoc analyses between subgroups can provide a
preliminary view of the possible effects of the medication.
However, higher-powered, prospectively designed stud-
ies should be conducted to confirm these findings. In
addition, the standard three-week duration of the studies
allowed for the initial assessment of the efficacy and
safety of medication, but longer-term studies need to be
performed in order to evaluate continuing efficacy and
safety. Our study demonstrated that aripiprazole is
effective across different patient subtypes based upon
the moderators of different subpopulations. However, we
did not specifically identify those patients who were more
(or less) likely to respond based on other potential
mediators during the study. Finally, head-to-head com-
parative studies are needed with other medications in
different subpopulations of patients with bipolar disorder
to allow for a better understanding of efficacy and safety
profiles and more informed choices when selecting
treatment for this diverse population of patients.
5. Summary
Choosing an appropriate treatment for patients with
bipolar disorder is challenging, especially as clinical
studies and practice suggest that not all types of manic
or mixed episodes respond the same to all medications.
The results of the post hoc analyses presented here
8 T. Suppes et al. / Journal of Affective Disorders xx (2007) xxxxxx
ARTICLE IN PRESS
Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
disorder, J. Affect. Disord. (2007), doi:10.1016/j.jad.2007.08.015
Page 8
support that aripiprazole may effectively and safely treat
a broad spectrum of patient subtypes experiencin g
manic or mixed episo des, including different levels of
co-occurring depressive symptoms, rapid cycling, and
psychotic symptoms. No gender differences were noted
in response patterns. Further prospective studies will be
necessary in order to confirm these findings.
Role of funding source
Funding for this study was provided by Bristol-Myers Squibb.
Editorial support was provided by Maria Soushko, PhD, Phase Five
Communicatio ns Inc., with funding provi ded by Bristol-Myers
Squibb.
Conflict of interest
Dr. Trisha Suppes has: received funding or medications for clinical
grants from Abbott Laboratories, AstraZene ca, GlaxoSmithKline
Pharmaceuticals, Janssen Pharmaceutica, JDS Pharmace uticals,
National Institute of Mental Health , Novartis Pharmaceuticals, Pfizer
Inc, Stanley Medical Research Institute, and Wyeth; received
honoraria for consulting and participation in advisory boards from
Abbott Laboratories, AstraZ eneca, Bristol -Myers Squibb, Eli Lilly
Research Laboratories, GlaxoSmit hKline Pharmaceuticals, Janssen
Pharmaceutica, JDS Phar maceutical s, Novartis Pha rmaceutic als,
Orth o-McNeil Pharmaceutical, Pfize r Inc, Shire Pharmaceutical,
Solvay, and UCB Pharma; received honoraria and reimbursement
for travel for speaking bureaus from AstraZ eneca and GlaxoSmith-
Kline; and has received royalties from Compact Clinicals. James
Eudicone and Ber it Carlson are employees of Bri stol-Myers Squibb.
Robert McQuade and Andrei Pikalo v III are employees of Otsuka
America Pharmaceut icals, Inc.
Acknowledgement
Editorial support was provided by Maria Soushko,
PhD, Phase Five Communications Inc., with funding
provided by Bristol-Myers Squibb.
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10 T. Suppes et al. / Journal of Affective Disorders xx (2007) xxxxxx
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Please cite this article as: Suppes, T. et al., Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I
disorder, J. Affect. Disord. (2007), doi:10.1016/j.jad.2007.08.015
Page 10
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    • "The data was stratified according to the severity of manic symptoms, the presence of depressive features, psychosis, and history of rapid cycling. The salutary effects of aripiprazole therapy were seen in these different subsets of cases with severe disease attributes, epitomizing that this agent has an important place in the treatment of bipolar diathesis [34]. Finally, while this article was in revision, a published meta-analysis showed that in both controlled and real-world settings, aripiprazole was superior to placebo and equal to active comparators in acute and stabilization phases of bipolar mania. "
    [Show abstract] [Hide abstract] ABSTRACT: Bipolar disorder is characterized by exacerbations of opposite mood polarity, ranging from manic to major depressive episodes. In the current nosological system of the Diagnostic and Statistical Manual – 5th edition (DSM-5), it is conceptualized as a spectrum disorder consisting of bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, and bipolar disorder not otherwise specified. Treatment of all phases of this disorder is primarily with mood stabilizers, but many patients either show resistance to the conventional mood stabilizing medications or are intolerant to their side-effects. In this setting, second-generation antipsychotics have gained prominence as many bipolar subjects who are otherwise treatment refractory show response to these agents. Aripiprazole is a novel antipsychotic initially approved for the treatment of schizophrenia but soon found to be effective in bipolar disorder. This drug is well studied, as randomized controlled trials have been conducted in various phases of bipolar disorders. Aripiprazole exhibits the pharmacodynamic properties of partial agonism, functional selectivity, and serotonin-dopamine activity modulation – the new exemplars in the treatment of major psychiatric disorders. It is the first among a new series of psychotropic medications, which now also include brexpiprazole and cariprazine. The current review summarizes the data from controlled trials regarding the efficacy and safety of aripiprazole in adult bipolar patients. On the basis of this evidence, aripiprazole is found to be efficacious in the treatment and prophylaxis of manic and mixed episodes but has no effectiveness in acute and recurrent bipolar depression.
    Full-text · Article · Apr 2016
  • Source
    • "In order to ascertain if SGA have similar efficacy in treating manic symptoms in mixed episodes as in pure mania, we computed SMD for SGA separately for these two conditions. For this analysis, we compared the effect sizes of seven of the nine included RCTs (Suppes et al., 2008; Khanna et al., 2005; McIntyre et al., 2009; Sachs et al., 2002; Tohen et al., 2002; Keck et al., 2003a Keck et al., , 2003b Berwaerts et al., 2012) that reported data for pure manic and mixed episodes separately (Fig. 4. Further, no significant differences were noted in the mean YMRS change scores for SGA between manic and mixed patients in each study (−0.00, 95% CI: −0.12, 0.12; Z¼ 0.02, p¼0.99) (Fig. 5). The SMD of mean change in depression scores in two trials, was statistically significant in favor of the SGA group compared to placebo (−0.30, 95% CI −0.47, −0.13). "
    [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: The literature on the treatment mixed episodes in Bipolar Disorder [BD] is sparse. Second generation antipsychotics [SGA] have documented efficacy in mania, but not mixed episodes. The objective of this meta-analysis was to ascertain the efficacy of SGA, either as mono- and/or adjunctive therapy, in the treatment of acute mixed episodes of BD, compared to placebo. METHODS: A MEDLINE search for English language publications of randomized controlled trials [RCTs] comparing SGA with placebo in the treatment of an acute manic/mixed episode of BD, during the period 1990-2012, was performed using the terms 'atypical antipsychotics', 'SGA', 'mixed episodes', 'dysphoric mania' and each SGA independently. 9 RCTs reporting data on 1289 mixed episode patients treated with aripiprazole, asenapine, olanzapine, paliperidone-ER, risperidone, and ziprasidone, either as monotherapy or as adjunctive therapy, versus placebo, for 3-6 weeks, were included in the meta-analysis. We extracted data on the number of patients, SGA, duration of study and mean change in mania and depression scores from baseline to endpoint. Standardized mean difference between SGA and placebo for the mean baseline-to-endpoint change in mania and depression rating scores was calculated, with a 95% confidence limit. RESULTS: SGA, either alone or in combination with mood stabilizers, had superior efficacy in treating manic symptoms of mixed episodes compared to placebo (-0.41, 95% CI -0.53, -0.30; overall effect p<0.00001). SGA were equally effective for manic symptoms in mixed episodes and pure mania (p=0.99). SGA had superior efficacy in treating depressive symptoms of mixed episodes (-0.30, 95% CI -0.47, -0.13; p<0.001) compared to placebo in two trials reporting this information. LIMITATIONS: Thirteen relevant studies could not be included as data for mixed-episodes were not presented separately. CONCLUSIONS: SGA are effective in treating acute mixed episodes of BD, with predominant manic symptoms. Their efficacy in treating depressed mixed episodes remains unclear.
    Full-text · Article · Jun 2013 · Journal of Affective Disorders
  • Source
    • "Conversely, antidepressant treatment to treat only depressive symptoms can induce a manic switch (Baldessarini et al., 2012; Fornaro et al., 2012; Pacchiarotti et al., 2011a; Valenti et al., 2011). The drugs that showed positive effects in the subset of patients with mixed mania as defined in DSM-IV in placebocontrolled trials (asenapine, olanzapine, and valproate) (Azorin et al., 2013; Baker et al., 2003; Nivoli et al., 2012; Swann et al., 1997; Yatham et al., 2013), and to some extent those that showed separation from placebo in pooled analysis (aripiprazole and ziprasidone) (Stahl et al., 2010; Suppes et al., 2008), may be the best candidates for the treatment of the newly defined DSM-5 mixed states. Of note, there are very few data on the use of quetiapine in acute mixed states but positive adjunctive longterm data (Vieta et al., 2012), and ziprasidone (Patkar et al., 2012) has been tested in depressive mixed states (which did not exist in the DSM-IV). "
    [Show abstract] [Hide abstract] ABSTRACT: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) nomenclature for the co-occurrence of manic and depressive symptoms (mixed states) has been revised in the new DSM-5 version to accommodate a mixed categorical-dimensional concept. The new classification will capture subthreshold non-overlapping symptoms of the opposite pole using a "with mixed features" specifier to be applied to manic episodes in bipolar disorder I (BD I), hypomanic, and major depressive episodes experienced in BD I, BD II, bipolar disorder not otherwise specified, and major depressive disorder. The revision will have a substantial impact in several fields: epidemiology, diagnosis, treatment, research, education, and regulations. The new concept is data-driven and overcomes the problems derived from the extremely narrow definition in the DSM-IV-TR. However, it is unclear how clinicians will deal with the possibility of diagnosing major depression with mixed features and how this may impact the bipolar-unipolar dichotomy and diagnostic reliability. Clinical trials may also need to address treatment effects according to the presence or absence of mixed features. The medications that are effective in treating mixed episodes per the DSM-IV-TR definition may also be effective in treating mixed features per the DSM-5, but new studies are needed to demonstrate it.
    Full-text · Article · Apr 2013 · Journal of Affective Disorders
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