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SYSTEMATIC REVIEW
Mood Stabilizers and Antipsychotics for Acute Mania:A Systematic Review and Meta-Analysis of Combination/Augmentation Therapy Versus Monotherapy
Yusuke Ogawa • Aran Tajika • Nozomi Takeshima •
Yu Hayasaka • Toshi A. Furukawa
Published online: 27 August 2014
� Springer International Publishing Switzerland 2014
Abstract
Background Pharmacotherapy remains the mainstay of
treatment for acute bipolar mania, but there are many
choices, including mood stabilizers (MSs) and antipsy-
chotics (APs).
Objective To provide an up-to-date and comprehensive
review of the efficacy, acceptability and adverse effects of
MSs and APs as combination or augmentation therapy
versus monotherapy with either drug class for the treatment
of acute mania.
Data Sources The Cochrane Central Register of Con-
trolled Trials, MEDLINE, PsycINFO, Scopus, and clinical
trial databases were searched for articles published
between the inception of the databases and July 1, 2014.
The following keywords were used: [bipolar disorder,
mania, manic, mixed bipolar, schizoaffective] combined
with the names of MSs and APs. The reference lists of all
the identified randomized controlled trials (RCTs), articles
that cited the identified trials, and recent systematic
reviews were also checked.
Study Selection Double-blind RCTs comparing MS and
AP as combination or augmentation therapy with either
monotherapy during the acute phase treatment of mania
were included in the present study. The electronic search
yielded 6,445 potential articles in September 2013 and 264
new references in an updated search performed in July
2014. Finally, 19 RCTs were considered eligible for our
meta-analyses: MS plus AP combination or augmentation
therapy was compared with MS monotherapy in 14 trials
(n = 3,651) and with AP monotherapy in 6 trials
(n = 606) [one study compared combination therapy ver-
sus both MS monotherapy and AP monotherapy].
Data Extraction The primary outcomes were the mean
change scores on validated rating scales for mania and all-
cause discontinuation at 3 weeks. The secondary outcomes
included response, remission, the mean change scores for
depression, dropouts due to adverse events and to ineffi-
cacy, and adverse events at 3 weeks and mean change
scores on validated rating scales at 1 week. Using random-
effects models, standardized mean difference (SMD), risk
ratio (RR) and numbers needed to treat with their 95 %
confidence intervals (CIs) were calculated.
Results Most patients included in trials comparing com-
bination/augmentation therapy versus MS monotherapy
had prior treatment with an MS, while more than 70 % of
participants in trials comparing combination/augmentation
therapy versus AP monotherapy had not been on medica-
tions or were washed out from their previous medication
before randomization. MS plus AP combination/augmen-
tation therapy was more effective than MS monotherapy in
terms of change in scores on mania rating scales at 3 weeks
(SMD -0.26; 95 % CI -0.36 to -0.15) and at 1 week
(SMD -0.17, -0.29 to -0.04). MS plus AP combination/
augmentation therapy was more effective than AP mono-
therapy at 3 weeks (SMD -0.31, -0.50 to -0.12), but not
at 1 week (SMD -0.22, -0.84 to 0.40). No significant
differences were seen between the combination/augmen-
tation therapy and either monotherapy group in study
withdrawal for any reason (MS ? AP vs. MS mono-
therapy: RR 0.99, 0.88–1.12; MS ? AP vs. AP mono-
therapy: RR 0.70, 0.47–1.04) or adverse events (MS ? AP
vs. MS monotherapy: RR 1.39, 0.97–1.99; MS ? AP vs.
AP monotherapy: RR 0.62, 0.27–1.40). The combination/
Y. Ogawa (&) � A. Tajika � N. Takeshima � Y. Hayasaka �T. A. Furukawa
Department of Health Promotion and Human Behavior,
Kyoto University Graduate School of Medicine/School of Public
Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
e-mail: [email protected]
CNS Drugs (2014) 28:989–1003
DOI 10.1007/s40263-014-0197-8
augmentation therapy was associated with more side
effects, especially with somnolence, while it did not
increase treatment-emergent depression.
Conclusions Combining MS and AP is more efficacious
and more burdensome than, but overall as acceptable as,
the continuation of MS or AP monotherapy, when either
monotherapy has not been successful. There is currently no
robust evidence to judge whether MS and AP combination
therapy is more efficacious than MS monotherapy as the
initial therapy for acutely manic patients without prior
medication.
Key Points
Adjunct antipsychotics (AP) to mood stabilizers
(MS) is more efficacious, associated with more side
effects than, but overall as acceptable as, the
continuation of MS monotherapy, when the
monotherapy has not been successful for acute
mania.
Combining MS and AP is more efficacious than, and
overall as acceptable as, AP monotherapy both as
first-line and second-line treatments of acute mania.
1 Introduction
Bipolar disorder, the eighteenth leading cause of disability
in the world [1], is a chronic disorder with an estimated
lifetime prevalence of around 1 % [2]. It is characterized
by recurrent manic and depressive episodes. In the fifth
edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) published in 2013, the chapter on
‘‘mood disorders’’ no longer exists and ‘‘bipolar and related
disorders’’ are distinguished clearly from ‘‘depressive dis-
orders’’. Additionally, the concept of mixed episode having
both symptoms of mania and depression that was present in
DSM-IV criteria has disappeared. Instead, a manic, hypo-
manic or depressive episode can be specified as ‘‘with
mixed features’’. These episodes of bipolar disorder dete-
riorate the sufferers’ functioning as well as their quality of
life. It also carries with it significant increases in morbidity,
socio-economic costs and risks of suicide [3].
Pharmacotherapy remains the mainstay of treatment for
acute bipolar mania, but there are many choices, including
mood stabilizers (MSs) and antipsychotics (APs). Several
guidelines for the treatment of acute mania recommend that
the first-line treatment for a manic episode should be a
monotherapy with a mood stabilizer, an antipsychotic agent
or another drug [4–6]. Combinations, as either two drugs
started together (combination therapy) or as a second drug
added on to an ongoing one (augmentation), are suggested
only for severe cases or as a second choice in patients for
whom monotherapy has been ineffective.
Two previous meta-analyses [7, 8] have shown a greater
efficacy of adding AP on MS than for MS alone during
manic phases. Unfortunately, these meta-analyses are now
outdated. They included only eight [7] and six [8] studies,
respectively, published before 2004, but several important
and large-scale randomized controlled trials (RCTs) on this
topic have been conducted since then. In addition, not only
remission but also the speed of onset is important for
treatment of acute mania because some patients show
dangerous behavior, but previous meta-analyses did not
evaluate efficacy at early timepoints (e.g. at 1 week).
Moreover, few meta-analyses on adverse effects, including
drug-induced depression [9], have been conducted, result-
ing in unclear guidelines for clinicians with regard to bal-
ancing benefits and risks when choosing among treatment
alternatives. Neither have subgroup analyses among dif-
ferent MSs been conducted, which adds another layer of
ambiguity in clinical decision recommendations. Further-
more, MS plus AP was compared against MS only, although
monotherapy with AP for acute mania has been broadly
provided in recent clinical practice, and no systematic
reviews or meta-analyses comparing MS plus AP versus AP
monotherapy for acute mania have been published so far.
The aim of the present study was, therefore, to update
and extend evidence regarding pharmacotherapy for acute
mania by comparing MS plus AP combination/augmenta-
tion therapy versus either monotherapy with regard to their
relative efficacy as well as their adverse effects.
2 Methods
2.1 Search Strategy, Inclusion Criteria, Data Extraction
Double-blind RCTs comparing MS plus AP combination or
augmentation therapy with either monotherapy during the
acute phase treatment of bipolar mania were identified by
searching the Cochrane Central Register of Controlled
Trials (CENTRAL), MEDLINE, PsycINFO, and Scopus
for articles published between the inception of the dat-
abases and September 20, 2013, and updated searches were
carried out in July 1, 2014. We used sensitive search
strategies for RCTs. We also searched clinical trial dat-
abases, such as ClinicalTrials.gov, the International Stan-
dard Randomized Controlled Trial Number Register
(ISRCTN) and the WHO International Clinical Trials
Registry Platform (ICTRP). The following phrases were
used: [bipolar disorder, mania, manic, mixed bipolar,
schizoaffective] and combined with the following MSs and
990 Y. Ogawa et al.
APs, including their brand names. We defined MSs as
drugs which are used for the long-term maintenance pro-
phylaxis and which are not APs. It has been known that
some APs have mood stabilizing effects. However, in this
review, we divided drugs into ’antipsychotics’ and ’mood
stabilizers other than antipsychotics’ to evaluate the effi-
cacy of combined drugs having different mechanisms. The
MSs included lithium, valproate and carbamazepine. The
APs included amisulpride, aripiprazole, asenapine, chlor-
promazine, clozapine, flupentixol, fluphenazine, haloperi-
dol, levomepromazine, olanzapine, paliperidone, perazine,
perphenazine, prochlorperazine quetiapine, risperidone,
sulpiride, ziprasidone, zotepine and zuclopenthixol. The
reference lists of all the identified RCTs, articles that cited
the identified trials, and recent systematic reviews were
checked.
All double-blind RCTs comparing AP plus MS combi-
nation or augmentation therapy with either monotherapy
during the acute phase treatment of bipolar mania were
included. Quasi-randomized trials (such as those allocating
treatment using alternate days of the week) were excluded.
No language or time restrictions were applied. In the
present review, acute treatment was defined as 3 (range, 2
to 6) weeks of treatment in both the efficacy and accept-
ability analyses, and longer-term studies were excluded if
they did not provide data for a period between 2–6 weeks.
Patients of both sexes and aged 18 years or older pre-
senting with a manic or mixed episode, with or without
psychotic features, of bipolar or schizoaffective disorder
according to any standardized diagnostic criteria were
included. We excluded participants with a concurrent pri-
mary diagnosis of another Axis I or II disorder or partici-
pants with a serious concomitant medical illness.
Two review authors independently examined the titles
and abstracts of all the publications obtained through the
above-described search strategy. The full articles of all the
studies identified by either of the review authors were
obtained and inspected by two review authors to identify
trials meeting the review criteria. Conflicts of opinion
regarding the eligibility of a study were discussed with a
third review author. Two independent review authors
extracted data from each study and assessed the risk of bias
using the Cochrane Collaboration ‘‘risk of bias’’ tool [10],
which pays particular attention to random sequence gen-
eration, allocation concealment, integrity of the blinding of
participants and study personnel, integrity of the blinding
of outcome assessments, the completeness of outcome
data, selective reporting, and other biases. Each item was
categorized as having a high risk of bias, a low risk of bias,
or an unclear risk of bias in each study. Any disagreements
were resolved through discussion with a third review
author. Where necessary, the authors of the original studies
were contacted for further information.
2.2 Types of Outcome Measures
Treatment focus of bipolar mania should include acute
symptoms of mania, behavioural disturbance and psychosis
[11]. In this review, we have focused on the first two, as
measured by the rating scales for mania used by all of the
included studies. The primary outcomes were (1) the mean
change scores on validated rating scales for mania, such as
the Young Mania Rating Scale (YMRS), and (2) dropouts
for any reason. Secondary outcomes included (1) response
of manic symptoms (measured as the total number of
patients who had a reduction in manic severity by at least
50 % of the baseline value), (2) remission (defined as B12
on the YMRS), (3) mean change scores on validated rating
scales for mania from baseline to the 1-week point, (4)
mean change scores on validated rating scales for depres-
sion, such as the Hamilton Depression Rating Scale
(HDRS) or the Montgomery-Asberg Depression Rating
Scale (MADRS), (5) dropouts due to adverse events, (6)
dropouts due to inefficacy, and (7) adverse events accord-
ing to individual reports, such as extrapyramidal symptoms
(EPS), tremor, treatment emergent depression, somnolence,
and weight gain. Except secondary outcome (3) (change
scores at 1-week point), the primary assessment time point
was set at 3 weeks after randomization, but if such data
were not available, we accepted data obtained between 2
and 6 weeks, giving preference to the time point closest to
3 weeks.
2.3 Data Synthesis and Statistical Analysis
We conducted 2 comparisons: Comparison 1: MS plus AP
combination/augmentation therapy versus MS mono-
therapy, and Comparison 2: MS plus AP combination/
augmentation therapy versus AP monotherapy.
We employed the random-effects model for the meta-
analyses [12] because we had anticipated a priori some
clinical heterogeneity among the populations and inter-
ventions that would be included in this study. The stan-
dardized mean difference (SMD) and its 95 % confidence
interval (CI) were calculated for continuous outcomes.
We analyzed the endpoint data separately when change
data were not available. For binary data, the risk ratio
(RR) and its 95 % CI were calculated. The number nee-
ded to treat (NNT) was calculated by taking the average
event rate among the controls and then applying the RR
to this rate.
When a study involved more than two relevant treatment
arms (e.g., two doses both within the standard range), we
combined the continuous data following the formula given
in Section 7.7.3.8 of the Cochrane Handbook for System-
atic Reviews of Interventions [10]. When a study involved
two co-therapy groups and a monotherapy group, we
Combination/Augmentation Therapy Versus Monotherapy for Acute Mania 991
divided the monotherapy group into two equal-sized groups
for subgroup analyses to avoid double-counting the same
subjects. All the data were analyzed based on an intention-
to-treat (ITT) principle: dropouts were always included in
this analysis. When participants were withdrawn from the
trial before the endpoint, it was assumed that their condi-
tion would have remained unchanged if they had stayed in
the trial. Whenever ITT data were presented by the authors,
they were preferred to ‘‘per protocol or completer’’ data
sets. We contacted the original study authors for missing
data. If the missing data could not be obtained, they were
imputed according to a validated method [13]. The intra-
class correlation coefficient (ICC) between the observed
numbers of responses and remission and the corresponding
numbers derived from this imputation method were cal-
culated to examine the validity of the method in this
clinical field. In the absence of supplemental data after
requests to the authors, the SDs were estimated from the
CI, t values or P values [10].
We assessed the heterogeneity first by a visual
inspection of the forest plots. We then calculated the I2
statistics [12]. In addition to the I2 statistic, we calcu-
lated the Chi2 statistic and its P value and considered the
direction and magnitude of the treatment effects. As the
Chi2 test is underpowered to detect heterogeneity in
meta-analyses with a small number of studies, a P value
of 0.10 was used as the threshold of statistical
significance.
We conducted the following pre-planned subgroup
analyses: (1) types of MSs and APs, and (2) mania
severity at baseline (divided according to the median of
the reported mean YMRS total scores at baseline). We
also conducted sensitivity analyses as follows: (1) exclu-
sion of trials in which the participants had been treated
with the target drugs without a washout period to evaluate
the efficacy of combination therapy (not augmentation
therapy), and (2) exclusion of trials with a high risk of
bias. We investigated the reporting bias by constructing
funnel plots and conducting an Egger’s test [14] when ten
or more studies were pooled for the primary outcomes.
The first subgroup analysis was conducted for all the
primary and secondary outcomes. The first sensitivity
analysis was conducted for both primary outcomes. The
second subgroup analysis, the second sensitivity analysis
and the funnel plot analysis were conducted for the pri-
mary efficacy outcome only.
We used SPSS version 20 (IBM Corporation, Somers,
NY, USA) to calculate the ICC, Review Manager Version
5.1 (Nordic Cochrane Centre, Cochrane Collaboration;
Copenhagen, Denmark; http://ims.cochrane.org/revman) to
perform the meta-analyses, and Stata version 12.1 (Stata
Corporation, College Station, TX, USA) to conduct the
Egger’s test.
3 Results
Figure 1 summarizes the study selection process. The
electronic search yielded 6,445 articles. We excluded 1,488
duplicate studies. After the titles and abstracts had been
inspected, the full text was retrieved and reviewed for 139
articles. One additional unpublished trial from the trial
registers and one conference abstract included in a previous
systematic review were also identified. We excluded 122
reports that did not meet the eligibility criteria. The
results of two completed studies were not reported [15, 16].
Finally, 19 RCTs, which included a total of 4,250 patients,
were included in the analysis. Fourteen studies [17–30]
(including 3,651 patients) compared MS plus AP combi-
nation/augmentation therapy versus MS monotherapy, and
6 studies (including 606 patients) compared MS plus AP
combination/augmentation therapy versus AP monotherapy
[19, 31–35] (one study [19] compared combination therapy
versus both MS monotherapy and AP monotherapy).
In July 2014 we updated the searches and a total of 264
new references were identified. On the basis of the infor-
mation provided in titles and abstracts, five potentially
relevant studies were noted; however, on retrieving the full
text papers, we found none of the studies to be eligible.
3.1 Study Characteristics and Quality Assessment
Table 1 summarizes the study characteristics of the inclu-
ded studies. The mean ages at the baselines of all the
included trials were under 43 years. Participants had
already been treated with MSs before randomization in
most studies in Comparison 1, although in one study [19]
no patient was on MS before inclusion into the study and
another study [26] set a washout phase. In comparison 2, of
the six included studies, most of the patients were not on
drug therapy before study inclusion in one study [19],
about half were not so in another [31], and two trials [32,
33] had set a washout period. All studies in Comparison 1
and half of the studies [19, 32, 35] in Comparison 2 were
sponsored by the pharmaceutical industry, and sponsorship
in the remainder of the studies was unclear [31, 33, 34].
Only a small amount of data could be obtained from one
old study [19] and one conference abstract [28]. More than
30 % of the patients had dropped out in 8 studies [17, 20–23,
29, 30] comparing combination/augmentation therapy vs.
MS monotherapy. Except for these two items (selective
outcome reporting and incomplete outcome data), none of
the studies were rated as having a high risk of bias according
to the risk of bias tool of the Cochrane Handbook [10]. The
ICC values between the observed versus the imputed num-
bers were 0.99 for response and 0.98 for remission.
Visual inspection of the funnel-plot for the primary
outcome (mean change scores in mania severity) was not
992 Y. Ogawa et al.
suggestive of a publication bias or other small study
effects, and the Egger’s test for bias was not significant
(P = 0.37) in Comparison 1. For Comparison 2, we did not
perform a funnel plot analysis because only six studies
were included.
3.2 Comparison 1. MS Plus AP Combination/
Augmentation Therapy Versus MS Monotherapy
3.2.1 Efficacy
MS plus AP combination/augmentation therapy was more
efficacious than MS monotherapy with regard to the
change in scores on the rating scales for mania (12 studies:
SMD -0.26, 95 % CI -0.36 to -0.15; I2 = 47 %; Fig. 2),
response (11 studies: RR 1.25, 1.14 to 1.36; I2 = 6 %;
NNT 10.1, 7.0 to 18.1), remission (12 studies: RR 1.17,
1.07 to 1.28; I2 = 23 %; NNT 15.7, 9.6 to 38.2) at 3 weeks
and the change in scores on the rating scales at 1 week (7
studies: SMD -0.17, -0.29 to -0.04; I2 = 33 %). Com-
bination/augmentation therapy with haloperidol, asenapine,
olanzapine, quetiapine or risperidone provided significantly
greater improvements in the YMRS scores than MS
monotherapy. The heterogeneity among the individual tri-
als was moderate, with an I2 estimate of 47 %, and was
statistically significant according to a Chi2 test (P = 0.03);
this was probably due to heterogeneity among two trials
examining aripiprazole [17, 27] and among three studies
Fig. 1 Study flow diagram. AP
antipsychotic, MS mood
stabilizer
Combination/Augmentation Therapy Versus Monotherapy for Acute Mania 993
Ta
ble
1C
har
acte
rist
ics
of
incl
ud
edtr
ials
Stu
dy
,re
gio
nP
opu
lati
on
Du
rati
on
(wee
k)
An
tip
sych
oti
cs,
mea
nd
ose
(ran
ge)
Mo
od
stab
iliz
ers,
blo
od
lev
elm
ean
(ran
ge)
,m
ean
do
seM
ean
age
(yea
r)B
asel
ine
mea
nN
Co
mple
ters
(%)
Co
mpar
iso
n1
.M
Sp
lus
AP
com
bin
atio
n/a
ug
men
tati
on
ther
apy
ver
sus
MS
mon
oth
erap
y
Ber
wae
rts
20
11
[17]
Asi
a,A
fric
a,E
uro
pe,
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C2
0.
Pri
or
trea
tmen
t:li
thiu
mo
rv
alpro
ate
6P
alip
erid
on
e8
.1(3
–1
2)
mg
Lit
hiu
mN
A(0
.6–
1.2
meq
/L),
NA
or
Val
pro
ate
NA
(50–125
meq
/L),
NA
40
.0Y
MR
S=
27
.01
50
60
Pla
ceb
oL
ith
ium
NA
(0.6
–1.2
meq
/L),
NA
or
Val
pro
ate
NA
(50–125
meq
/L),
NA
40
.0Y
MR
S=
27
.01
50
66
Bri
sto
l-M
yer
s
Sq
uib
b2
00
8[1
8]
Afr
ica,
Asi
a,E
uro
pe
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C1
6.
Pri
or
trea
tmen
t:li
thiu
mo
rv
alpro
ate
12
Ari
pip
razo
le1
0m
g(fi
xed
do
se)
Lit
hiu
mN
A,
NA
or
Val
pro
ate
NA
,N
A
44
.4N
A1
81
67
Pla
ceb
oL
ith
ium
NA
,N
A
or
Val
pro
ate
NA
,N
A
44
.9N
A1
89
69
Gar
fin
kel
19
80
[19]
Can
ada
Fei
ghner
pri
mar
yaf
fect
ive
dis
ord
erm
ania
,in
pat
ien
ts.
Pri
or
trea
tmen
t:m
ost
rece
ived
no
dru
gth
erap
yex
cep
t4
pat
ien
tsta
kin
gn
euro
lep
tics
3H
alo
per
ido
l2
4.2
mg
Lit
hiu
m0
.81
meq
/L,
NA
37
.0N
A7
NA
Pla
ceb
oL
ith
ium
1.2
meq
/L,
NA
41
.5N
A7
43
Ho
ust
on
20
09
[20]
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
mix
edep
isod
ew
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C1
6.
Pri
or
trea
tmen
t:d
ival
pro
ex
6O
lanza
pin
e14.6
(5–20)
mg
Val
pro
ate
71
(75
–12
5)
meq
/L,
NA
38
.6Y
MR
S=
21
.41
01
57
Pla
ceb
oV
alp
roat
e8
6(7
5–
12
5)
meq
/L,
NA
38
.5Y
MR
S=
20
.41
01
59
Sac
hs
20
02
[21]
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C2
0,
inp
atie
nts
Pri
or
trea
tmen
t:li
thiu
mo
rv
alpro
ate
3H
alo
per
ido
l6
.2(2
–1
2)
mg
Lit
hiu
m0
.7,
(0.6
–1
.4)
meq
/L,
1,0
41
mg
or
Div
alp
roex
76
.2(5
0–
12
0)
meq
/L,
1,4
36
mg
42
.7Y
MR
S=
27
.35
34
7
Ris
per
idone
3.8
(1–6)
mg
Lit
hiu
m0.7
,(0
.6–1.4
)m
eq/L
,1
,052
mg
or
Div
alp
roex
65
.4(5
0–
12
0)
meq
/L,
1,4
18
mg
41
.4Y
MR
S=
28
.05
26
5
Pla
ceb
oL
ith
ium
0.8
,(0
.6–
1.4
)m
eq/L
,1
,077
mg
or
Div
alp
roex
77
.3(5
0–
12
0)
meq
/L,
1,3
12
mg
42
.1Y
MR
S=
28
.05
15
1
Sac
hs
20
04
[22]
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C2
0,
inp
atie
nts
.
Pri
or
trea
tmen
t:al
mo
stal
lw
ere
trea
ted
wit
ha
mo
od
-sta
bil
izer
3Q
uet
iap
ine
50
4(2
00
–8
00
)m
gL
ith
ium
0.7
8,
(0.7
–1.0
)m
eq/L
,N
A
or
Val
pro
ate
65
(50
–10
0)
meq
/L,N
A
39
.6Y
MR
S=
31
.59
16
2
Pla
ceb
oL
ith
ium
0.7
1,
(0.7
–1.0
)m
eq/L
,N
A
or
Val
pro
ate
65
(50
–10
0)
meq
/L,N
A
41
.3Y
MR
S=
31
.11
00
49
994 Y. Ogawa et al.
Ta
ble
1co
nti
nu
ed
Stu
dy
,re
gio
nP
opu
lati
on
Du
rati
on
(wee
k)
An
tip
sych
oti
cs,
mea
nd
ose
(ran
ge)
Mo
od
stab
iliz
ers,
blo
od
lev
elm
ean
(ran
ge)
,m
ean
do
seM
ean
age
(yea
r)B
asel
ine
mea
nN
Co
mple
ters
(%)
Sac
hs
20
12
[23]
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,Y
MR
SC
18
,in
-an
do
utp
atie
nts
Pri
or
trea
tmen
t:li
thiu
mo
rd
ival
pro
ex
3Z
ipra
sidone
90.1
(40
–16
0)
mg
Lit
hiu
m0
.8(0
.6–
1.2
)m
eq/L
,1
,012
mg
or
Div
alp
roex
74
.3(5
0–
12
5)
meq
/L,
1,2
96
mg
41
.4Y
MR
S=
27
.24
58
72
Pla
ceb
oL
ith
ium
0.8
(0.6
–1
.2)
meq
/L,
1,0
21
mg
or
Div
alp
roex
72
.8(5
0–
12
5)
meq
/L,
1,2
43
mg
41
.5Y
MR
S=
26
.02
22
81
Sze
ged
i2
01
2[2
4]
Asi
a,A
ust
rali
a,E
uro
pe,
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C2
0.
Pri
or
trea
tmen
t:li
thiu
mo
rv
alpro
ate
12
Ase
nap
ine
11
.8(1
0–
20
)m
gL
ith
ium
NA
(0.6
–1.2
meq
/L),
NA
or
Val
pro
ate
NA
(50–125
meq
/L),
NA
39
.6Y
MR
S=
28
.01
59
38
Pla
ceb
oL
ith
ium
NA
(0.6
–1.2
meq
/L),
NA
or
Val
pro
ate
NA
(50–125
meq
/L),
NA
39
.0Y
MR
S=
28
.21
67
33
To
hen
20
02
[25]
Can
ada,
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C1
6,
in-
and
ou
tpat
ien
ts
Pri
or
trea
tmen
t:li
thiu
mo
rv
alpro
ate
6O
lanza
pin
e10.4
(5–20)
mg
Lit
hiu
m0
.76
(0.6
–1.2
)m
eq/L
,N
A
or
Val
pro
ate
63.6
(50–125)
meq
/L,
NA
40
.7Y
MR
S=
22
.32
29
70
Pla
ceb
oL
ith
ium
0.8
2(0
.6–
1.2
)m
eq/L
,N
A
or
Val
pro
ate
74.7
(50–125)
meq
/L,
NA
40
.4Y
MR
S=
22
.71
14
72
To
hen
20
08
[26]
Au
stra
lia,
Eu
rop
e
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C2
0,
ou
tpat
ien
ts.
Pri
or
trea
tmen
t:1
-wee
kw
ash
out
ph
ase
6O
lanza
pin
e26.9
(20–30)
mg
Car
bam
azep
ine
NA
,618
mg
40.1
YM
RS
=2
7.9
58
74
Pla
cebo
Car
bam
azep
ine
NA
,717
mg
41.3
YM
RS
=2
6.6
60
70
Vie
ta2
00
8[2
7]
Eu
rop
eD
SM
-IV
bip
ola
rl
dis
ord
erm
anic
or
mix
edep
isod
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C1
6,
ou
tpat
ien
ts
Pri
or
trea
tmen
t:li
thiu
mo
rv
alpro
ate
6A
rip
ipra
zole
19
(15
–3
0)
mg
Lit
hiu
m0
.76
(0.6
–1.0
)m
eq/L
,1
,160
mg
or
Val
pro
ate
68.2
(50–125)
meq
/L,
1,2
25
mg
42
.2Y
MR
S=
23
.22
53
79
Pla
ceb
oL
ith
ium
0.7
2(0
.6–
1.0
)m
eq/L
,9
85
mg
or
Val
pro
ate
68.4
(50–125)
meq
/L,
1,1
79
mg
41
.7Y
MR
S=
23
.01
31
85
Wei
sler
20
03
[28]
NA
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
ode,
inpat
ients
.
Pri
or
trea
tmen
t:li
thiu
m
3Z
ipra
sidone
NA
(80
–16
0m
g)
Lit
hiu
mN
A(0
.8–
1.2
meq
/L),
NA
(ran
ge
C1
8)
NA
10
26
9
Pla
ceb
oL
ith
ium
NA
(0.8
–1.2
meq
/L),
NA
(ran
ge
C1
8)
NA
10
37
2
Yat
ham
20
03
[29]
Afr
ica,
Can
ada,
Eu
rop
e
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
ico
rm
ixed
epis
od
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C2
0,
inp
atie
nts
.
Pri
or
trea
tmen
t:li
thiu
m,
div
alp
roex
or
carb
amaz
epin
e
3R
isper
idone
4(m
edia
n)
(1–
6)
mg
Lit
hiu
mN
A,
NA
,D
ival
pro
exN
A,
NA
or
Car
bam
azep
ine
NA
,N
A
37
(med
ian
)Y
MR
S=
29
.37
56
4
Pla
ceb
oL
ith
ium
NA
,N
A,
Div
alp
roex
NA
,N
A
or
Car
bam
azep
ine
NA
,N
A
42
(med
ian
)Y
MR
S=
28
.37
64
7
Combination/Augmentation Therapy Versus Monotherapy for Acute Mania 995
Ta
ble
1co
nti
nu
ed
Stu
dy
,re
gio
nP
opu
lati
on
Du
rati
on
(wee
k)
An
tip
sych
oti
cs,
mea
nd
ose
(ran
ge)
Mo
od
stab
iliz
ers,
blo
od
lev
elm
ean
(ran
ge)
,m
ean
do
seM
ean
age
(yea
r)B
asel
ine
mea
nN
Co
mple
ters
(%)
Yat
ham
20
07
[30]
Asi
a,A
fric
a,C
anad
a,E
uro
pe,
Un
ited
Sta
tes
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
icep
isod
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C2
0,
inpat
ien
ts
Pri
or
trea
tmen
t:li
thiu
mo
rv
alpro
ate
6Q
uet
iap
ine
42
3
(B8
00
mg
)
Lit
hiu
m0
.79
(0.7
1.0
)m
eq/L
,N
A
or
Val
pro
ate
67
(50
–10
0)
meq
/L,N
A
38
.9Y
MR
S=
32
.31
06
67
Pla
ceb
oL
ith
ium
0.7
8(0
.7–
1.0
)m
eq/L
,N
A
or
Val
pro
ate
77
(50
–10
0)
meq
/L,N
A
40
.1Y
MR
S=
32
.61
05
59
Co
mpar
iso
n2
.M
Sp
lus
AP
com
bin
atio
n/a
ug
men
tati
on
ther
apy
ver
sus
AP
mo
no
ther
apy
Bie
der
man
19
79
[31]
Asi
a
RD
Csc
hiz
oaf
fect
ive
dis
ord
erm
anic
type
wit
hp
sych
osi
s,in
pat
ien
ts.
Pri
or
trea
tmen
t:h
alf
rece
ived
neu
role
pti
csan
dh
alf
too
kn
om
edic
atio
n
5H
alo
per
ido
l3
3m
gL
ith
ium
1.0
8(0
.7–
1.6
)m
eq/L
,1
,620
mg
32
.3M
anic
Sca
le=
24
22
18
6
Hal
op
erid
ol
36
mg
Pla
ceb
o2
9.6
Man
icS
cale
=2
43
18
10
0
Bou
rin
20
09
[32]
Asi
a,A
fric
a,E
uro
pe
DS
M-I
Vb
ipo
lar
ld
iso
rder
man
icep
isod
e,w
ith
or
wit
ho
ut
psy
cho
sis,
YM
RS
C20,
inpat
ients
.
Pri
or
trea
tmen
t:pri
or
tom
edic
atio
nw
ash
ou
t
6Q
uet
iap
ine
NA
(40
0–8
00
mg)
Lit
hiu
mN
A,
NA
37
.9Y
MR
S=
29
.91
73
85
Qu
etia
pin
eN
A(4
00
–8
00
mg)
Pla
ceb
o3
8.8
YM
RS
=3
0.0
18
37
9
Cho
u1
99
9[3
3]
Un
ited
Sta
tes
DS
M-I
II-R
bip
ola
rl
dis
ord
erm
anic
epis
od
e,w
ith
psy
cho
sis,
inp
atie
nts
.
Pri
or
trea
tmen
t:m
ost
sub
ject
sre
ceiv
edan
tipsy
choti
cm
edic
atio
nan
dp
lann
ed1
wee
kd
rug
-fre
ep
erio
d(b
ut
itw
aso
ften
tru
nca
ted
bec
ause
of
clin
ical
dec
om
pen
sati
on
)
3H
alo
per
ido
l1
5.9
(5–
25)
mg
Lit
hiu
m1
.07
meq
/L,
NA
34
.6M
SR
S=
17
72
2N
A
Hal
op
erid
ol
14
.5(5
–2
5)
mg
Pla
ceb
o3
4.6
MS
RS
=1
69
19
NA
Gar
fin
kel
19
80
[18]
Can
ada
Fei
ghner
pri
mar
yaf
fect
ive
dis
ord
erm
ania
,in
pat
ien
ts.
Pri
or
trea
tmen
t:m
ost
rece
ived
no
dru
gth
erap
yex
cep
t4
pat
ien
tsta
kin
gn
euro
lep
tics
3H
alo
per
ido
l2
4.2
mg
Lit
hiu
m0
.81
meq
/L,
NA
37
.0N
A7
NA
Hal
op
erid
ol
28
mg
Pla
ceb
o3
7.0
NA
7N
A
Moll
er1
98
9[3
4]
Eu
rope
ICD
-9an
dR
DC
acu
tem
ania
or
sch
izom
anic
syn
dro
me
wit
ho
rw
ith
ou
tp
sych
osi
s.
Pri
or
trea
tmen
t:u
ncl
ear
3H
alo
per
ido
l2
4m
g(fi
xed
do
se)
Car
bam
azep
ine
NA
,600
mg
34.0
BR
MA
S=
24
.31
11
00
Hal
op
erid
ol
24
mg
(fix
edd
ose
)P
lace
bo
32
.8B
RM
AS
=2
6.3
98
9
Mull
er-
Oer
linghau
sen
20
00
[35
]
Eu
rop
e
ICD
-10
man
icep
iso
de
wit
ho
rw
ith
ou
tp
sych
osi
so
rsc
hiz
oaf
fect
ive
dis
ord
er,
man
icty
pe
(80
%w
ere
bip
ola
ro
rsc
hiz
oaf
fect
ive
dis
ord
er),
inpat
ients
.
Pri
or
trea
tmen
t:st
andar
dneu
role
pti
cspre
fera
bly
only
hal
op
erid
ol
and
/or
per
azin
e
3H
alo
per
ido
lan
d/o
rp
eraz
ine
8.2
mg
(HE
D)
Val
pro
ate
80
.3(5
0–
10
0)
meq
/L,
NA
39
.0Y
MR
S=
30
.96
99
0
Hal
op
erid
ol
and
/or
per
azin
e1
0.4
mg
(HE
D)
Pla
ceb
o3
7.0
YM
RS
=3
0.9
67
84
AP
anti
psy
cho
tic
agen
ts,B
RM
AS
Bet
h-R
afae
lsen
-Sca
lefo
rM
ania
,H
ED
hal
op
erid
ol
equ
ival
ent
do
se,M
RS
Man
iaR
atin
gS
cale
,M
Sm
oo
dst
abil
izer
s,M
SR
SM
anic
Sta
teR
atin
gS
cale
,N
ran
do
miz
edn
um
ber
of
par
tici
pan
ts,
NA
no
tav
aila
ble
,R
DC
Res
earc
hD
iag
no
stic
Cri
teri
a,Y
MR
SY
ou
ng
Man
iaR
atin
gS
cale
996 Y. Ogawa et al.
examining olanzapine [20, 25, 26]. The subgroup hetero-
geneity among the APs, however, was not noticeable
(I2 = 0 %; Fig. 2).
Combination/augmentation therapy was more effective
than MS monotherapy with regard to the change in scores
for depression (6 studies: SMD -0.21, -0.37 to -0.06).
Looking at individual drugs, olanzapine combination/aug-
mentation therapy was significantly more efficacious than
MS monotherapy with regard to depressive symptoms.
3.2.2 Trial Withdrawal
There was no significant difference between combination/
augmentation therapy and MS monotherapy in terms of
trial withdrawal for any reason (13 studies: RR 0.99, 0.88
to 1.12; I2 = 37 %; Fig. 3). The heterogeneity among the
AP subgroups was significant (I2 = 61.2 %, P = 0.01),
and qualitative differences were noted. For quetiapine and
risperidone, the dropout rates revealed a significant
Fig. 2 MS ? AP versus MS Alone: Mean Severity of Mania: Change Scores. AP antipsychotic, MS mood stabilizer
Combination/Augmentation Therapy Versus Monotherapy for Acute Mania 997
superiority of combination/augmentation therapy to
monotherapy, while ziprasidone combination/augmenta-
tion therapy showed disadvantages over monotherapy in
terms of trial withdrawals for any reason.
There was no significant difference between combi-
nation/augmentation therapy and MS monotherapy in
terms of withdrawal because of the development of
adverse events (12 studies: RR 1.39, 0.97–1.99). Looking
at individual APs, the dropout rates due to adverse
events were higher for paliperidone and ziprasidone
combination/augmentation therapy, compared with
monotherapy.
The dropout rates due to inefficacy showed a statistically
significant superiority for the combination/augmentation
treatment, compared with MS monotherapy (12 studies:
RR 0.62, 0.47–0.82; NNT 34.5, 24.7–72.7).
Fig. 3 MS ? AP versus MS alone: dropout for any reason. AP antipsychotic, MS mood stabilizer
998 Y. Ogawa et al.
3.2.3 Adverse Events
Significantly more participants in the combination/aug-
mentation therapy group experienced at least one side effect
(8 studies: RR 1.18, 1.08–1.30; I2 for subgroup, 28.0 %). In
terms of individual adverse effects, the addition of AP to MS
significantly increased somnolence (9 studies: RR 2.46,
1.91–3.18; I2 for subgroup, 0 %) and weight gain (7 studies:
RR 3.72, 2.46–5.63; I2 for subgroup, 0 %), with low heter-
ogeneity across APs. With regard to EPS, the pooled esti-
mates were not significant but were heterogeneous among
APs for EPS (7 studies: RR 1.55, 0.84–2.85; I2 for subgroup
75.0 %, P = 0.001). Adding haloperidol (2 studies: RR
6.01, 1.55–23.4) and aripiprazole (1 study: RR 2.03,
1.26–3.25) significantly increased EPS, compared with MS
monotherapy. There was no robust difference between
combination/augmentation therapy and MS monotherapy in
terms of the development of tremor (8 studies: RR 1.40,
1.00–1.95; I2 for subgroup, 0 %) or Depression (9 studies:
RR 0.97, 0.66–1.42; I2 for subgroup, 2.8 %)
3.2.4 Subgroup and Sensitivity Analyses for the Primary
Efficacy Outcome
When classified according to individual MSs, no significant
subgroup heterogeneity in the mean change scores was
observed among the MSs (6 comparisons: Chi2 = 3.90,
P = 0.14, I2 = 48.7 %). For carbamazepine only, there
was no significant difference between combination therapy
and MS monotherapy, possibly because of the small sam-
ple size (1 study, 117 participants: SMD 0.06, -0.31 to
0.42). There was no subgroup heterogeneity between the
groups with a baseline YMRS \ 28 or C 28 (11 studies:
= 0.40, P = 0.53, I2 = 0 %).
After excluding 8 studies with a high risk of bias
because of incomplete outcome data, the results were
similar but lost their statistical significance (5 studies:
SMD -0.19, -0.40 to 0.03). There was just one study in
which the participants had washout from medications
before randomization [26].
3.3 Comparison 2. MS Plus AP Combination/
Augmentation Therapy Versus AP Monotherapy
3.3.1 Efficacy
Three trials [31–33] comparing lithium plus AP combina-
tion therapy with AP monotherapy reported the mean
change scores. Combination therapy with lithium was more
efficacious than AP monotherapy with regard to the mean
change scores for mania (3 studies: SMD -0.31, -0.50 to
-0.12; Fig. 4). One trial [35] comparing valproate plus AP
combination therapy with AP monotherapy reported only
the mean endpoint scores. Combination therapy with val-
proate was more effective than AP monotherapy with
regard to the endpoint score (1 study: SMD -0.50, -0.85
to -0.16; Fig. 4). Combination/augmentation therapy with
either lithium or valproate was more effective than AP
monotherapy with regard to response (4 studies: RR 1.24,
1.11 to 1.39; NNT 6.8, 4.3 to 15.5) and remission (2
studies: RR 1.28, 1.12 to 1.47; NNT 6.3, 3.8 to 14.8). Only
one trial [34] reported a mania score change at 1 week, and
there was no significant difference in the mean change
scores between lithium plus haloperidol combination
therapy and haloperidol monotherapy (1 study: SMD
-0.22, -0.84 to 0.40). Only one trial [32] reported a
depression score change, and there was no significant dif-
ference in the mean change scores for depression between
Fig. 4 MS ? AP versus AP alone: mean severity of mania. AP antipsychotic, MS mood stabilizer
Combination/Augmentation Therapy Versus Monotherapy for Acute Mania 999
lithium plus quetiapine combination therapy and quetiapine
monotherapy (1 study: SMD -0.15, -0.35 to 0.06).
3.3.2 Trial Withdrawal
There were no significant differences between combina-
tion/augmentation therapy with any of the MSs and AP
monotherapy in terms of trial withdrawal for any reason (4
studies: RR 0.70, 0.47–1.04; Fig. 5), the development of an
adverse events (4 studies: RR 0.62, 0.27–1.40) or inefficacy
(4 studies: RR 0.44, 0.12–1.69).
3.3.3 Adverse Events
Only one or two studies were available for analyses of
individual side effects. According to a report by Bourin
[32], adding lithium to quetiapine increased tremor and
somnolence (RR 3.17, 1.54–6.55; and RR 2.33, 1.13–4.77,
respectively). Adding MS to AP did not appear to increase
EPS (2 studies: RR 0.99, 0.57–1.72), depression (1 study:
RR 2.12, 0.19–23.12) or weight gain (RR 0.42, 0.08 to
2.15).
3.3.4 Subgroup and Sensitivity Analyses for the Primary
Efficacy Outcome
Because of the small number of relevant studies, we were
unable to perform either subgroup analyses or sensitivity
analysis to exclude studies with a high risk of bias. After
excluding trials without a washout period, combination
therapy remained significantly more effective than AP
monotherapy (2 studies: SMD -0.32, -0.52 to -0.12) and
as acceptable as monotherapy (1 study: RR 0.71, 0.45 to
1.11).
4 Discussion
4.1 Overall Findings
We identified and included 19 relevant RCTs, more than
twice the number of RCTs included in the previous reviews
[7, 8], examining MS plus AP combination/augmentation
therapy during the acute phase of the treatment of mania.
We compared the MS plus AP combination/augmentation
therapy not only against MS monotherapy, as in the pre-
vious reviews, but also against AP monotherapy, which
appears to be an increasingly popular treatment choice [4–
6]. Based on our meta-analyses, MS plus AP combination/
augmentation therapy demonstrated a greater efficacy than
either MS or AP monotherapy in reducing manic severity
and increasing response and remission at 3 weeks, while
there were no differences between the combination/aug-
mentation therapy and either monotherapy in terms of trial
withdrawal for any reason or due to adverse events. The
resulting NNTs suggested that only 10 patients receiving
MS monotherapy need to have AP added and only 7
patients receiving AP monotherapy need to have MS added
in order for one additional patient to show a 50 % or
greater reduction in his or her manic severity during the
acute phase. These results were robust to effect moderators,
such as baseline mania severity (in Comparison 1) and the
washout period (in Comparison 2).
These results are consistent with those of previous meta-
analyses [7, 8] showing that combination/augmentation
therapy resulted in a higher efficacy, compared with MS
monotherapy. Our analysis showed that there were no
significant differences between combination/augmentation
therapy and MS monotherapy in terms of trial withdrawal
for any reason and due to adverse events, which is
Fig. 5 MS ? AP Versus AP Alone: Dropout For Any Reason. AP antipsychotic, MS mood stabilizer
1000 Y. Ogawa et al.
consistent with the results of meta-analyses by Smith et al.
[7], while Scherk et al. [8] showed that add-on therapy
resulted in a significantly reduced dropout rate for any
reason. These findings may be due to the fact that in more
recent trials the patients who were treated with AP plus MS
had dropout rates that were similar to those receiving MS
monotherapy.
Adding AP to MS was more effective than MS mono-
therapy in reducing manic severity at 1 week while there
was no significant difference in the mean change scores for
mania between AP plus MS combination/augmentation
therapy and AP monotherapy. One reason for the differ-
ence may be differences in the speed of onset of effects
between the two regimens. Some RCTs reported that APs
were more effective than MSs in rating scale changes at
week 1 [36–39].
Adding AP to MS was also more effective than MS
monotherapy in reducing depressive symptoms during
acute mania. It has been sometimes suggested that drug
treatments for mania may be associated with a risk of
switching to depression [9]. However, our analysis sug-
gested that there was no evidence indicating that the
addition of AP to MS increased treatment emergent
depression but reduced depressive symptoms more than
MS monotherapy. On the other hand, there was only one
trial comparing combination therapy with AP monotherapy
in terms of depression scores, which were not significantly
different.
We included patients with mixed episode in this review.
Mixed episode in DSM-IV criteria having both symptoms
of mania and depression disappeared in DSM-5. However,
mixed episode in former diagnostic criteria would now
meet definition of ‘‘manic episode with mixed features’’ of
bipolar 1 disorder in DSM-5, so it is reasonable that
patients with mixed episode were included in this review
and changes of diagnostic criteria would not affect our
results.
4.2 Differences Among Individual Drugs
The subgroup heterogeneity across different APs as
adjuncts to MS was small for efficacy but substantive for
acceptability; adding risperidone or quetiapine to MS sig-
nificantly reduced trial dropouts for any reason, while
ziprasidone increased them. Of note, risperidone and que-
tiapine were among the five agents that were individually
found to offer adjunctive advantages over MS monotherapy
in terms of efficacy as well.
With regard to adverse effects, overall, the combination/
augmentation therapy appeared to cause more adverse
effects than either monotherapy. Either adding AP or MS to
the other monotherapy increased, somnolence. Individual
APs and MSs appeared to have differential adverse effect
profiles, but the inadequate reporting of adverse effects in
the original studies prohibited a comprehensive assess-
ment. For adverse events, Smith et al. [7] conducted meta-
analyses only for weight gain, and Scherk et al. [8] con-
ducted meta-analyses only for somnolence. These results
were consistent with our analyses.
4.3 Limitations
There are some limitations to our analysis. First and fore-
most, most patients included in comparison 1 had prior
treatment with an MS. In other words, the design of almost
all the trials in comparison 1 compared continuing MS
monotherapy or the addition of AP in patients who had a
breakthrough recurrent manic episode despite maintenance
therapy with MS, or whose manic episode did not respond
to initial treatments with MS monotherapy. Therefore,
there is currently no robust evidence that combination
therapy is more efficacious than MS monotherapy as initial
pharmacotherapy for acutely manic patients without prior
medication. Arguably, it is only natural to add something
new to something which had already failed in treating a
manic episode, and these results provide no guidance as to
whether it is better to start with two drugs from the very
beginning. On the other hand, more than 70 % of partici-
pants in comparison 2 had not been on medications or were
washed out from their previous medication before ran-
domization. We were able to conduct sensitivity analyses
for excluding trials without a washout period, which
showed combination therapy remained significantly more
effective than, and as acceptable as, AP monotherapy.
Secondly, our primary analyses considered different
MSs as one group, both within individual studies and
across studies. Admittedly lithium, valproate and carbam-
azepine have different mechanisms of action and may have
different combinatory efficacies when used with different
APs. However, our analytical policy seems defensible
because the subgroup analyses between MSs didn’t show
heterogeneity. Furthermore, a recent multiple-treatments
meta-analysis of monotherapy for mania [40] showed that
there were no significant differences among these MSs for
efficacy or acceptability.
Thirdly, most of the trials included in this review were
sponsored by the pharmaceutical industry. None of the
studies were clearly performed without industry support.
Therefore, the possibility of a sponsorship bias in favor of
their product cannot be excluded, and this may have
worked in favor of the combination/augmentation therapy
because the sponsor was most often the manufacturer of the
added drug.
Lastly, we could not conduct a meta-analysis of many of
the pre-planned outcomes for trials comparing combina-
tion/augmentation therapy versus AP monotherapy because
Combination/Augmentation Therapy Versus Monotherapy for Acute Mania 1001
the number of relevant trials was small and, moreover,
most of them reported only part of the outcomes that we
had set for this review. Furthermore, most of them were
conducted in or before 2000 and were rated as having an
unclear risk of bias for many items. Consequently, we need
more caution in arguing for the greater efficacy of com-
bination therapy over AP monotherapy.
5 Conclusions
In summary, we have collected the largest body of ran-
domized evidence to date comparing MS plus AP combi-
nation/augmentation therapy against either monotherapy
alone. In addition to our primary outcomes of efficacy and
acceptability, we also provided detailed examinations of
side effects, including treatment-emergent depression. This
type of information, which was not reported in previous
systematic reviews, is crucial for making treatment choices
in the real world.
The clinical implications of our review are as follows:
on average, combination/augmentation of AP and MS in
treating acute mania or adding AP to MS when the latter is
not satisfactory is more efficacious than and as acceptable
as MS or AP monotherapy. However, combination/aug-
mentation therapy is associated with more side effects,
especially somnolence. Different APs may be associated
with different adverse events; for example, adding halo-
peridol and aripiprazole was associated with more EPS. On
the other hand, adding risperidone or quetiapine to MS
showed advantages over MS monotherapy in terms of not
only efficacy but also the additional advantage of reducing
trial dropout. These differences in benefits and risks must
be taken into consideration when making treatment choices
for individual patients.
There are several research implications as well. First,
future studies should provide more detailed and uniform
evaluations of adverse effects. Second, studies about the
first-line treatment (i.e. whether to use combination ther-
apy, rather than either monotherapy) are required to answer
the urgent clinical question of how to treat drug-naive
patients with acute mania. Such studies appear all the more
justified in view of the small NNTs of the combination
therapy over monotherapies. Third, more and better trials
are needed, especially comparing MS plus AP combination
therapy against AP monotherapy, which appears to be more
and more frequently practiced of late.
Acknowledgments YO, AT and NT have received honoraria for
speaking at meetings sponsored by Eli Lilly. YH has no conflicts of
interest. TAF has received lecture fees from Eli Lilly, Meiji, Mochida,
MSD, Pfizer and Tanabe-Mitsubishi, and consultancy fees from Se-
kisui and Takeda Science Foundation. He is diplomate of the Acad-
emy of Cognitive Therapy. He has received royalties from Igaku-
Shoin, Seiwa-Shoten and Nihon Bunka Kagaku-sha. The Japanese
Ministry of Education, Science, and Technology, the Japanese Min-
istry of Health, Labor and Welfare, and the Japan Foundation for
Neuroscience and Mental Health have funded his research projects.
No sources of funding were used to assist with the preparation of the
manuscript.
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