Psychiatry 2008; 165:1316-1325

(published online April 1, 2008; doi: 10.1176/appi.ajp.2008.07101560)

2008 American Psychiatric Association
Efficacy of Adjunctive Aripiprazole to Either Valproate or Lithium in Bipolar
Mania Patients Partially Nonresponsive to Valproate/Lithium Monotherapy: A
Placebo-Controlled Study
Eduard Vieta, M.D., Ph.D., Caroline Tjoen, M.S., Robert D. McQuade, Ph.D.,
William H. Carson Jr., M.D., Ronald N. Marcus, M.D., Raymond Sanchez, M.D.,
Randall Owen, M.D., and Laurence Nameche, M.S., M.B.A.
Abstract

OBJECTIVE: The authors evaluated the efficacy and safety of adjunctive aripiprazole in
bipolar I patients with mania partially nonresponsive to lithium/valproate monotherapy.
METHOD: This multicenter, randomized, placebo-controlled study included outpatients
experiencing a manic or mixed episode (with or without psychotic features). Patients with
partial nonresponse to lithium/valproate monotherapy (defined as a Young Mania Rating
Scale total score 16 at the end of phases 1 and 2, with a decrease of 25% between phases)
with target serum concentrations of lithium (0.61.0 mmol/liter) or valproate (50125
g/ml) were randomly assigned in a 2:1 ratio to adjunctive aripiprazole (N=253; 15 or 30
mg/day) or placebo (N=131) for 6 weeks. RESULTS: Mean improvement from baseline in
Young Mania Rating Scale total score at week 6 (primary endpoint) was significantly
greater with aripiprazole (13.3) than with placebo (10.7). Significant improvements in
Young Mania Rating Scale total score with aripiprazole versus placebo occurred from
week 1 onward. In addition, the mean improvement in Clinical Global Impression Bipolar
Version (CGI-BP) severity of illness (mania) score from baseline to week 6 was
significantly greater with aripiprazole (1.9) than with placebo (1.6). Discontinuation rates
due to adverse events were higher with aripiprazole than with placebo (9% versus 5%,
respectively). Akathisia was the most frequently reported extrapyramidal symptom-related
adverse event and occurred significantly more frequently among those receiving
aripiprazole (18.6%) than among those receiving placebo (5.4%). There were no significant
differences between treatments in weight change from baseline to week 6 (+0.55 kg and
+0.23 kg for aripiprazole and placebo, respectively; last observation carried forward).
CONCLUSIONS: Adjunctive aripiprazole therapy showed significant improvements in
mania symptoms as early as week 1 and demonstrated a tolerability profile similar to that of
monotherapy studies.
Introduction

Mood stabilizers in combination with atypical antipsychotics are a first-line treatment

approach for severe manic or mixed bipolar episodes (13). For mildly ill patients with
bipolar disorder, combination therapies are generally a second-line approach (1), but mood
stabilizer and antipsychotic combinations are widely used (1, 4). The efficacy of such
regimens has been demonstrated in several randomized, controlled studies (510);
however, some studies failed to separate the primary efficacy parameters from placebo (5
7) and most did not prospectively ensure patient partial nonresponse using well-defined
rigorous criteria.
Studies have shown that the atypical antipsychotic aripiprazole is effective and well
tolerated in the treatment of acute bipolar mania (11, 12), and it has shown superiority to
haloperidol in response rates and tolerability in a 12-week acute mania trial (13).
Furthermore, aripiprazole monotherapy was superior to placebo in maintaining efficacy in
patients with a recent manic/mixed episode who were stabilized and maintained on a
regimen of aripiprazole for at least 6 weeks (14, 15). However, in a fixed-dose study of
aripiprazole in the treatment of acute mania, aripiprazole did not separate from placebo
despite similar symptom improvements to those seen in other studies (Otsuka America
Pharmaceutical, Inc., unpublished 2003 data), and aripiprazole monotherapy did not
demonstrate superior efficacy to placebo at endpoint in two studies in bipolar depression
(16).
The present study is the first randomized, controlled study to investigate the efficacy and
safety of adjunctive aripiprazole and either lithium or valproate compared with lithium or
valproate plus placebo for the treatment of patients with bipolar I mania who were partially
nonresponsive to lithium/valproate monotherapy.
Method

Patients
Eligible patients were ages 18 years or older with DSM-IV criteria for bipolar I disorder,
manic or mixed type (with or without psychotic features); diagnosis was confirmed by the
Mini International Neuropsychiatric Interview. Patients had a history of at least one
previous manic or mixed episode that required hospitalization and/or treatment with a mood
stabilizer or antipsychotic.
Exclusion criteria were hospitalization for current manic or mixed episode for more than 3
weeks; previous nonresponse to treatments for manic symptoms; diagnosis of bipolar II
disorder or rapid cycling bipolar disorder; history of substance abuse or dependence;
significant risk of committing suicide; recent treatment with a long-acting antipsychotic; or
known sensitivity to any of the study drugs. All patients provided written informed consent.

Study Design and Treatments

Phase 1 was a screening period (328 days, with an extension to 42 days with permission)
during which medications other than lithium or valproate were discontinued. For patients
not currently receiving a mood stabilizer, the investigators determined which medication to
initiate. Patients were required to have a therapeutic serum level of lithium (0.61.0
mmol/liter) or valproate (50125 g/ml) and a Young Mania Rating Scale total score 16 at
the end of screening. Median duration of treatment with lithium/valproate in phase 1 was 16
days (range=369 days) in the placebo group and 16 days (range=176 days) in the
aripiprazole group.
Phase 2 was a 2-week baseline period during which patients continued to receive open-label
lithium or valproate monotherapy. At week 2, patients with confirmed partial nonresponse
(defined as a Young Mania Rating Scale total score 16 during phase 1 and at the end of
phase 2, with a decrease of 25% between phases) were randomly assigned in a 2:1 ratio to
receive either adjunctive aripiprazole (15 mg/day) or adjunctive placebo during the 6-week,
double-blind phase (phase 3), stratified by type of mood stabilizer. Aripiprazole dose could
be adjusted after week 1 (to 30 mg/day) based on tolerability or clinical response.
During baseline mood stabilizer treatment (phase 2), lorazepam (4 mg/day) or equivalents
were permitted during week 1 and week 2 (3 mg/day). Propranolol (maximum dose of 20
mg t.i.d.) was also permitted. During double-blind treatment (phase 3), patients were
permitted the use of benzodiazepines (2 mg/day of lorazepam or equivalents) for a
maximum of 10 days during the first 4 weeks only. Anticholinergic therapy (benztropine
mesylate or equivalents, 2 mg/day) and propranolol (maximum dose of 20 mg t.i.d., not to
be taken within 8 hours of efficacy or safety assessment) were permitted for extrapyramidal
symptoms. Propranolol for the treatment of heart disease was also permitted among those
patients receiving it prior to enrollment.
Assessments
During double-blind treatment, efficacy was assessed at day 4 and thereafter at weekly
intervals until week 6. The primary efficacy measure was the mean change from baseline to
week 6 in Young Mania Rating Scale total score (last observation carried forward). The key
secondary measure was the mean change from baseline to week 6 in Clinical Global
Impression Bipolar Version (CGI-BP) severity of illness (mania) score. Other secondary
measures at week 6 included rates of response (proportion of patients demonstrating 50%
improvement from baseline in Young Mania Rating Scale total score) and remission
(proportion of patients achieving Young Mania Rating Scale total score 12); mean change
from preceding phase in CGI-BP scores (mania, depression, and overall); mean change
from baseline in CGI-BP severity of illness (overall) score and (depression) score; mean
change from baseline in Positive and Negative Syndrome Scale (PANSS) total score and
PANSS positive, negative, cognitive, and hostility subscale scores; mean change from
baseline in Montgomery-sberg Depression Rating Scale (MADRS) total score; proportion
of patients with emergent depression (defined as a MADRS total score 18 plus a 4-point
increase from baseline in any two consecutive assessments); and time from random

assignment to response and remission. A priori analyses were also performed on subgroups
of patients receiving lithium or valproate. A post-hoc analysis was conducted to evaluate
remission using criteria from both illness poles (proportion of patients achieving Young
Mania Rating Scale total score 12 plus a MADRS total score 8). Mean change from baseline
to week 6 in Longitudinal Interval Follow-Up EvaluationRange of Impaired Function
Tool total score was also evaluated.
Safety evaluations were based on reports of adverse events, vital signs, electrocardiogram
(ECG) findings, and weight and laboratory assessments. Severity of extrapyramidal
symptoms was assessed using the Simpson-Angus Scale, the Barnes Rating Scale for DrugInduced Akathisia, and the Abnormal Involuntary Movement Scale (AIMS).
Statistical Analyses
A sample size of 360 (aripiprazole: N=240; placebo: N=120) was chosen to provide 90%
power to detect a difference of 3.2 points in the mean change from baseline to week 6 in
Young Mania Rating Scale total score between adjunctive aripiprazole and adjunctive
placebo. Analyses were performed on both the last observation carried forward and the
observed data. Continuous efficacy measures were evaluated using analysis of covariance
(ANCOVA) and adjusted for treatment, baseline measurement, and type of mood stabilizer.
A hierarchical testing procedure was used to preserve the significance level at 0.05. If the
difference between aripiprazole and placebo on the primary efficacy measure was
statistically significant (p0.05), then testing of the difference between aripiprazole and
placebo on the key secondary efficacy measure could proceed at =0.05. Testing of all other
secondary endpoints was performed at the =0.05 significance level without adjustment for
multiple comparisons and multiple testing. Binary outcomes were analyzed using CochranMantel-Haenszel general association statistics stratified by type of mood stabilizer. All tests
were two-sided.
Time from random assignment to response and remission were evaluated by survival
analyses and Kaplan-Meier survival curves. Log-rank tests stratified by type of mood
stabilizer were used to compare survival distributions between treatment groups. Parameter
estimates and 95% confidence intervals (CI) for the hazard ratio were obtained using a Cox
regression model with treatment as a covariate, stratified by type of mood stabilizer.
Post-hoc analyses were conducted to calculate an effect size (d) using the Cohen method for
paired samples (17) minus the difference in mean change in Young Mania Rating Scale total
score between the placebo and the aripiprazole group, divided by the pooled standard
deviation (SD). The number needed to treat, or the average number of patients who needed
to be treated to show response in one additional patient, was also calculated. Post-hoc
analysis of the change from baseline across all 11 items of the Young Mania Rating Scale
was also conducted.
Results

Patient Characteristics and Disposition

The progress of patients through the trial is shown in Figure 1. In total, 384 patients
completed the screening and baseline phase and were randomly assigned to double-blind
treatment with either placebo (N=131) or aripiprazole (N=253). Of the patients who
discontinued the study during the baseline phase (N=54), 21 did so because they achieved
response with lithium/valproate monotherapy (and thus could not meet criteria for study
continuation). Double-blind treatment was completed by 85% and 79% of patients
randomly assigned to placebo and aripiprazole, respectively. Discontinuation rates due to
adverse events were higher for patients in the aripiprazole group than for patients in the
placebo group (9% versus 5%; p=0.200). Baseline demographic and clinical characteristics
of patients were similar between treatment groups (Table 1).

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Figure 1. CONSORT Diagram

a
One patient received double-blind study medication during
phase 2 in error.

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TABLE 1

Study Treatments
Of the patients randomly assigned to double-blind treatment (N=384), 157 were receiving
lithium and 227 were receiving valproate. For the patients assigned to adjunctive
aripiprazole, the mean dose of aripiprazole during week 6 was 19.0 mg/day. For the lithium
subgroup, the mean dose of lithium the day before starting adjunctive treatment was 994
mg/day and 1,119 mg/day for the placebo and aripiprazole arms, respectively. Mean lithium
serum levels at baseline in these two groups were 0.77 mmol/liter (SD=0.17) and 0.78
mmol/liter (SD=0.22), respectively. The mean dose of lithium during week 6 of doubleblind treatment was 985 mg/day and 1,160 mg/day for the placebo and aripiprazole groups,
respectively. Mean lithium serum levels at week 6 (last observation carried forward) were
similar in both groups (placebo: 0.72 mmol/liter [SD=0.22]; aripiprazole: 0.76 mmol/liter
[SD=0.35]; t= 0.87, df=140, p=0.385). A similar proportion of patients in both arms had a
serum lithium level within the therapeutic range at endpoint (placebo: 68.0%; aripiprazole:
69.9%). For the valproate subgroup, the mean dose the day before starting adjunctive
treatment was 1,175 mg/day and 1,180 mg/day for the placebo and aripiprazole arms,
respectively. The mean serum valproate level at baseline in the two groups was 77.2 g/ml
(SD=23.4) and 77.8 g/ml (SD=21.0), respectively. The mean dose of valproate during
week 6 of double-blind treatment was 1,179 mg/day and 1,225 mg/day for the placebo and
aripiprazole groups, respectively. Similar mean serum valproate levels at endpoint (week 6;
last observation carried forward) were seen between the two groups (placebo: 68.35 g/ml

[SD=23.92]; aripiprazole: 68.23 g/ml [SD=23.63]; t=0.04, df=161, p=0.971). A similar

proportion of patients in both arms had a serum valproate level within the therapeutic range
at endpoint (placebo: 78.8%; aripiprazole: 80.0%).
More than 40% of patients received concomitant CNS medication. The most frequently
taken CNS medications were anxiolytics (placebo: 24.6%; aripiprazole: 20.9%) and other
analgesics and antipyretics (placebo: 23.1%; aripiprazole: 21.3%). A total of 47 (18.6%)
patients in the aripiprazole group received a concomitant medication for the potential
treatment of extrapyramidal symptoms, compared with nine (6.9%) patients in the placebo
group.
Efficacy
At week 6, adjunctive aripiprazole showed significantly greater improvements from
baseline in Young Mania Rating Scale total score than placebo (13.3 [SD=7.9] versus
10.7 [SD=7.6]; F=9.54, df=1, 373, p<0.01; d=0.33) (Figure 2). Aripiprazole plus mood
stabilizer produced significantly greater improvements from baseline in Young Mania
Rating Scale total score than lithium/valproate monotherapy by week 1 and at all
subsequent endpoints (p<0.05) (Figure 2). In a post-hoc analysis, adjunctive aripiprazole
did not worsen manic symptoms as measured by an item analysis of the Young Mania
Rating Scale, and in addition demonstrated significant improvements relative to placebo on
six of the 11 items: elevated mood, sexual interest, irritability, speech, disruptive/aggressive
behavior, and insight (Figure 3).

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Figure 2. Mean Change From Baseline in Young Mania Rating

Scale Total Score for Bipolar Mania Patients Randomly
Assigned to Adjunctive Treatment With Aripiprazole or Placebo
(Efficacy Sample)a
a

Last observation carried forward. Mean scores at baseline were

22.7 and 23.1 for placebo and aripiprazole, respectively.
*p<0.05. **p<0.01.

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Figure 3. Mean Change From Baseline in Young Mania Rating

Scale Individual Item Scores (Efficacy Sample)
*p<0.05. **p<0.01. ***p<0.001.

A priori analyses of each subgroup showed that adjunctive aripiprazole with valproate
produced significantly (p<0.05) greater improvements in Young Mania Rating Scale total
score than placebo from day 4 through week 6 (14.0 [SD=7.8] versus 10.7 [SD=7.9];
F=9.06, df=1, 222, p<0.01; last observation carried forward). For the lithium subgroup, the
improvement from baseline at week 6 with aripiprazole was numerically, albeit not
significantly, greater than with adjunctive placebo (12.4 [SD=8.1] versus 10.8 [SD=7.1];
F=1.40, df=1, 149, p=0.238; last observation carried forward). In the observed data,
adjunctive aripiprazole produced significantly greater improvements in Young Mania
Rating Scale total score than adjunctive placebo at week 5 (13.7 [SD=6.8] versus 10.2
[SD=7.5]; F=6.24, df=1, 114, p<0.05) and week 6 (14.7 [SD=6.5] versus 10.2 [SD=7.4];
F=11.00, df=1, 113, p0.001).
Adjunctive aripiprazole was also associated with significant reductions in CGI-BP severity
of illness (mania) score versus placebo (Table 2). Response rates were significantly higher
with adjunctive aripiprazole than with placebo at week 5 (2=5.79, df=1, p0.05; last
observation carried forward) (Figure 4). At week 6, 62.8% of the aripiprazole group had
responded to treatment, compared with 48.5% of the placebo group ( 2=7.07, df=1, p<0.01;
last observation carried forward), and the number needed to treat was 7. Compared with
placebo, aripiprazole also produced significantly higher remission rates at weeks 1, 3, 4, 5,
and 6 (Figure 4). At week 6, the remission rate was 66.0% for aripiprazole and 50.8% for
placebo (2=8.18, df=1, p<0.01; last observation carried forward), and the number needed to
treat was 7. Post-hoc analysis using more stringent remission criteria (Young Mania Rating
Scale total score 12 plus a MADRS total score 8) also showed significantly higher
remission rates with aripiprazole than with placebo at week 6 (50.2% versus 36.4%; 2=6.44,
df=1, p<0.05; last observation carried forward). Similar rates were observed in the lithium
and valproate subgroups, although the differences between the two were not statistically
significant (lithium: 51.0% versus 34.7%; 2=3.51, df=1, p=0.061; valproate: 49.7% versus
37.5%; 2=3.06, df=1, p=0.080).

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TABLE 2

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Figure 4. Rate of Response (A) and Remission (B) in Bipolar

Patients With Mania Randomly Assigned to Adjunctive
Treatment With Aripiprazole or Placebo (Efficacy Sample)
a

Defined as 50% improvement in Young Mania Rating Scale

total score (last observation carried forward).
b

Defined as achieving a Young Mania Rating Scale total score

12 (last observation carried forward).
c

Day 4: N=97.

Day 4: N=191.

*p<0.05. **p0.01.

Time to response (number of events for aripiprazole: 178 [72.1%]; for placebo: 83 [63.8%];
hazard ratio=1.45) and time to remission (number of events for aripiprazole: 185 [74.9%];
for placebo: 87 [66.9%]; hazard ratio=1.48), as evaluated by survival curves, were both
significantly in favor of aripiprazole (2=7.84, df=1, p<0.01 and 2=9.04, df=1, p<0.01,
respectively).
Adjunctive aripiprazole also produced a significantly greater improvement than placebo in
the CGI-BP severity of illness (overall) score at week 6 (p<0.05; last observation carried
forward) and significantly greater change than placebo from preceding phase in CGI-BP
severity of illness (overall) and (mania) scores (both p values <0.05; last observation carried
forward) (Table 2). The improvement over placebo in MADRS score seen with aripiprazole
was not statistically significant at endpoint (last observation carried forward). Analysis of
the observed data demonstrated statistically significant improvements in MADRS scores for
adjunctive aripiprazole versus adjunctive placebo at week 1 (2.0 [SD=4.2] versus 0.2
[SD=5.8]; F=10.79, df=1, 343, p<0.01), week 5 (3.8 [SD=4.9] versus 2.6 [SD=5.6];
F=4.03, df=1, 303, p<0.05), and week 6 (3.5 [SD=6.2] versus 1.7 [SD=6.6]; F=5.90,
df=1, 302, p<0.05).
The proportion of patients with emergent depression was significantly lower in the
aripiprazole arm than the placebo arm (7.7% versus 16.9%; 2=7.61, df=1, p<0.01).
Similarly, fewer patients reported emergent depression in the aripiprazole arm for both the
lithium subgroup (7.8% versus 24.0%; 2=7.61, df=1, p<0.01) and valproate subgroup,
although the difference in the valproate subgroup was not statistically significant (7.6%
versus 12.5%; 2=1.42, df=1, p=0.233).
Significantly greater improvements from baseline to week 6 were evident for aripiprazole
compared with placebo in PANSS total score and PANSS positive, cognitive, and hostility
subscale scores (p0.05; last observation carried forward), although there was no significant
difference between treatments in PANSS negative subscale scores (Table 2). There was a
significant difference between groups in mean change from baseline to week 6 in
Longitudinal Interval Follow-Up EvaluationRange of Impaired Function Tool total score
favoring aripiprazole versus placebo (1.8 versus 1.0; p=0.046).

Safety
During double-blind treatment, 53.8% (N=70) of patients in the adjunctive placebo group
and 62.1% (N=157) of patients in the adjunctive aripiprazole group reported at least one
treatment-emergent adverse event (p=0.140). Adverse events occurring at an incidence 5%
in either treatment group are shown in Table 3.

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TABLE 3

During double-blind treatment, serious adverse events were reported for 3.2% of
aripiprazole patients and 2.3% of placebo patients; most frequent were psychiatric disorders
typical of the patient population (aripiprazole: 2.4%; placebo: 2.3%). Most serious adverse
events were judged to be unrelated or unlikely to be related to study medication.
Patients treated with adjunctive aripiprazole showed more extrapyramidal symptoms than
patients in the placebo group. Adverse events related to treatment-emergent extrapyramidal
symptoms were reported in 28.1% (N=71) of the aripiprazole group and 13.8% (N=18) of
the placebo group. Of these patients, 25.4% (N=18) of the aripiprazole group and 22.2%
(N=4) of the placebo group had resolved the adverse event by study end. The most
frequently reported extrapyramidal symptom-related adverse event was akathisia
(aripiprazole: 18.6%; placebo: 5.4%). Other extrapyramidal symptom-related adverse events
occurred in <10% of patients in either group: tremor (placebo: 6.2%; aripiprazole: 9.1%);
extrapyramidal disorder (placebo: 0.8%; aripiprazole: 4.7%); hypertonia (placebo: 0%;
aripiprazole: 0.4%); hypokinesia (placebo: 0%; aripiprazole: 0.4%); muscle spasms

(placebo: 0.8%; aripiprazole: 2.0%); dyskinesia (placebo: 0.8%; aripiprazole: 0.4%); and
muscle twitching (placebo: 0%; aripiprazole: 0.4%). The lithium subgroup showed higher
rates of akathisia (aripiprazole: 28.3%; placebo: 4.0%) and tremor (aripiprazole: 13.2%;
placebo: 8.0%) than the valproate subgroup (aripiprazole: 11.6%; placebo: 6.3% and
aripiprazole: 6.1%; placebo: 5.0%, respectively). Akathisia was generally mild to moderate
in severity (aripiprazole: 15.8%; placebo: 4.6%); severe symptoms were reported in 2.8%
and 0.8% of aripiprazole and placebo patients, respectively. For aripiprazole patients who
reported akathisia with a maximum severity of mild, moderate, and severe, the
corresponding median highest Barnes Rating Scale for Drug-Induced Akathisia score was 2,
3, and 4, respectively. The majority of akathisia in the aripiprazole group began in the first 3
weeks of treatment (89.4%). Akathisia occurring during double-blind treatment led to
discontinuation in 13 aripiprazole patients (5.1%) and one placebo patient (0.8%). By the
end of double-blind treatment, akathisia had resolved in 15 out of the 47 patients (31.9%) in
the aripiprazole group and one out of the seven patients (14.3%) in the placebo group
reporting this symptom. The median duration of resolved akathisia events was 8 days. For
those subjects in the aripiprazole arm whose akathisia resolved during the study, two had
their study medication dose adjusted (one patient received a dose reduction and one patient
discontinued the study). Permitted concomitant medications (e.g., benztropine, propranolol)
for akathisia were administered in 11 patients (73.3%). Akathisia resolved without
intervention in three patients. The one patient in the placebo arm whose akathisia resolved
at the end of the double-blind treatment phase had a dose reduction but did not receive any
concomitant medication to treat the akathisia.
During adjunctive treatment, significant mean changes from baseline to the end of week 6
(last observation carried forward) were seen in Simpson-Angus Scale total scores (placebo:
baseline score=10.5, change in score=0.07; aripiprazole: baseline score=10.5, change in
score=0.73; F=9.05, df=1, 370, p<0.01) and Barnes Rating Scale for Drug-Induced
Akathisia scores (placebo: baseline score=0.18, change in score=0.11; aripiprazole: baseline
score=0.15, change in score=0.30; F=5.03, df=1, 370, p=0.026). Mean changes in AIMS
total scores were not significantly different between treatment groups (placebo: baseline
score=0.18, change in score= 0.10; aripiprazole: baseline score=0.25, change in
score=0.08; F=3.57, df=1, 370, p=0.060).
Small changes from baseline in body weight were observed with aripiprazole (+0.55 kg
[SD=2.66]) and placebo (+0.23 kg [SD=3.51]) at endpoint (last observation carried
forward), with no statistically significant differences between groups (p=0.331). There were
similar findings in the observed data (aripiprazole: +0.67 kg [SD=2.77]; placebo: +0.41 kg
[SD=3.64]; p=0.499). There were no significant treatment differences in the mean change in
weight from baseline to week 6 (last observation carried forward) in the lithium or valproate
subgroups. The percentage of patients showing clinically significant weight gain (7%
increase in weight from baseline to week 6; last observation carried forward) was similar in
the two groups: 3.9% (N=5) in the placebo arm and 3% (N=7) in the aripiprazole arm.
There were similar findings in the observed data and in the lithium and valproate
subgroups.

There were no clinically meaningful differences between treatments in laboratory

parameters, including total cholesterol, high- and low-density lipoprotein cholesterol,
glucose and triglycerides, and serum prolactin levels. Adjunctive aripiprazole plus
valproate/lithium treatment was not associated with any clinically relevant changes in vital
sign measurements or any ECG abnormalities.

Discussion

Aripiprazole as adjunctive therapy to lithium or valproate is efficacious and well-tolerated

for patients with manic or mixed episodes of bipolar I disorder who were partially
nonresponsive to lithium/valproate monotherapy. Reduction in mania symptoms, as
measured by change from baseline in Young Mania Rating Scale total score, was
significantly greater with adjunctive aripiprazole than with placebo. Importantly,
aripiprazole improved symptoms as early as week 1, since rapid symptom relief is an
established therapeutic goal in the management of bipolar mania. Consistent with a
previously published Young Mania Rating Scale item analysis in an acutely manic
population (18), the present study shows that aripiprazole ameliorated the core symptoms of
irritability and disruptive aggressiveness in an outpatient population. These symptoms can
lead to challenges in maintaining healthy social and family interactions for patients with
bipolar disorder.
Aripiprazole also showed statistically significant improvements on several other key
indicators of clinical efficacy. A significantly greater proportion of patients in the
aripiprazole group versus placebo group met criteria for remission (Young Mania Rating
Scale total score 12). Even in the post-hoc analysis using stricter remission criterion (Young
Mania Rating Scale total score 12 plus a MADRS total score 8), the difference between
aripiprazole and placebo was statistically significant. Furthermore, time to remission was
achieved sooner with adjunctive aripiprazole than with placebo and aripiprazole produced
significantly greater remission and response rates than placebo at weeks 3 and 5,
respectively.
Interestingly, the percentage of aripiprazole patients meeting criteria for remission was
higher than the percentage meeting criteria for response (66.0% versus 62.8%). This
illustrates the effect of baseline Young Mania Rating Scale score on outcome, as patients in
this study started with a relatively lower Young Mania Rating Scale total score (placebo:
22.7; aripiprazole: 23.1) than patients in other acute mania studies (Young Mania Rating
Scale total score 30). It also reflects the difference between the two measures (response

rates measure relative effect, while remission rates measure absolute effect) and highlights
the importance of assessing both response and remission in bipolar mania (19).
These results compare favorably to similar trials investigating the adjunctive use of atypical
agents with valproate or lithium in which risperidone (8), olanzapine (20), and quetiapine
(9) improved Young Mania Rating Scale total score versus adjunctive placebo. The findings
reported here are particularly significant as this study adopted more rigorous criteria for
nonresponse, plus a 2-week baseline phase to confirm lithium/valproate monotherapy partial
nonresponse. Furthermore, while previous studies have shown positive results, others have
failed to demonstrate efficacy on the primary efficacy endpoints (57).
This study was designed to detect a treatment difference between aripiprazole and placebo
in the total population and was not powered to detect treatment differences between
aripiprazole and placebo in subgroup analyses. Nonetheless, adjunctive aripiprazole showed
treatment differences from placebo in both valproate and lithium subgroups. In analyses of
the last observations carried forward, treatment differences were significant in the valproate
but not the lithium subgroup; in analyses of the observed data, treatment differences were
significant in both subgroups. This finding is not unique to aripiprazole, since a previous
study of adjunctive olanzapine and lithium/valproate versus lithium/valproate alone also
failed to show significant difference in response between the adjunctive olanzapine group
and the lithium subgroup (20).
Importantly, there was significantly less emergent depression in the aripiprazole group than
in the placebo group, suggesting that improvement in mania was not associated with a
destabilization into depression, a key challenge in treating bipolar disorder (21). Moreover,
aripiprazole was associated with improvements in psychosocial functionality, suggesting
that improved efficacy may translate into better social and family outcomes.
From a clinical standpoint, it is important to establish the safety and tolerability of
adjunctive therapies, even if tolerability as monotherapy is well established. Aripiprazole
plus lithium/valproate was well tolerated and adverse events were similar to those observed
with aripiprazole monotherapy (1114). Of particular interest is the greater incidence of
akathisia in the subgroup of patients taking lithium, although the study was not powered to
detect differences between subgroups. However, most reports were mild to moderate in
intensity and confirmed by Barnes analysis. The majority of akathisia events occurred early
in the study, suggesting potential sensitivity to the initial dose of aripiprazolea lower
starting dose may have been more tolerable. Additionally, akathisia resolved by the end of
double-blind treatment in one third of patients. As some events resolved spontaneously, one
might consider whether some treatment-emergent akathisia events were actually true
akathisia. Assessments of akathisia, as currently defined in clinical trials nomenclature,
might be capturing clinical features related to other syndromes, such as activation or anxiety
symptoms. Adjunctive aripiprazole was not associated with increases in body weight
compared with placebo, or with clinically significant weight gain, consistent with previous
studies of aripiprazole monotherapy (1113). This may have particular clinical relevance as
both lithium and valproate are associated with weight gain (22, 23).

This is the most rigorous study to date in terms of clearly demonstrating partial nonresponse
to an optimal dose of lithium/valproate monotherapy in a well-defined, prospective manner.
Another strength of this study is the relatively low discontinuation rate during double-blind
treatment. Study limitations include the fact that rapid-cycling bipolar patients were
excluded, patients were not randomly assigned to lithium or valproate subgroups, and the
study was not powered to compare subgroups. Also, the longer-term benefits of this
combination therapy need to be established.
Conclusion

Aripiprazole as adjunctive therapy to valproate/lithium was shown to provide a greater

improvement in mania symptoms as early as week 1 than with lithium or valproate alone.
The safety and tolerability profile of adjunctive aripiprazole was similar to that observed in
previous aripiprazole monotherapy studies in patients with bipolar mania. Aripiprazole in
combination with valproate/lithium is an effective and generally well-tolerated treatment for
patients with manic or mixed episodes of bipolar I disorder partially nonresponsive to
lithium/valproate monotherapy.
Footnotes
Received Oct. 4, 2007; revisions received Dec. 18, 2007, and Feb. 4, 2008; accepted Feb.
29, 2008 (doi: 10.1176/appi.ajp.2008.07101560). From the Clinical Institute of
Neuroscience, Hospital Clinic, University of Barcelona, Institut d"Investigacions
Biomdiques August Pi i Sunyer (IDIBAPS), Centro de Investigacin Biomdica En Red de
Salud Mental (CIBER-SAM), Barcelona, Spain; Bristol-Myers Squibb, Braine-lAlleud,
Belgium; Otsuka Pharmaceutical Development and Commercialization, Inc., Princeton,
N.J.; Bristol-Myers Squibb, Wallingford, Conn.; and Bristol-Myers Squibb, RueilMalmaison, France. Address correspondence and reprint requests to Dr. Vieta, Clinical
Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel
170/Rossello 140, 08036 Barcelona, Spain; evieta{at}clinic.ub.es
(e-mail).
Supported by Bristol-Myers Squibb (Princeton, N.J.) and Otsuka Pharmaceutical Co., Ltd.
(Tokyo). The authors thank Michelle ODonovan, Ph.D., and Ogilvy Healthworld Medical
Education for their assistance in preparing this manuscript.
Dr. Vieta has served as a consultant for AstraZeneca, Bial, Bristol-Myers Squibb, Eli Lilly,
GlaxoSmithKline, Janssen Pharmaceutica, Lundbeck, Merck-Sharp and Dohme, Novartis,
Organon, Otsuka, Pfizer, Sanofi-Aventis, Servier, and UCB Pharmaceuticals and has been a
speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen
Pharmaceutica, Lundbeck, Novartis, Otsuka, Pfizer, Sanofi-Aventis, and Servier. Ms.

Tjoen, Mr. Nameche, and Drs. Marcus, Sanchez, and Owen are employees of BristolMyers Squibb. Drs. McQuade and Carson are employees of Otsuka Pharmaceutical
Development and Commercialization, Inc.
Clinical Trial Registration: clinicaltrials.gov identifier: NCT00257972.

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