E Cacy of Modern Antipsychotics in Placebo-Controlled Trials in Bipolar Depression: A Meta-Analysis

International Journal of Neuropsychopharmacology (2010), 13, 5–14.
Copyright f CINP 2009 R E V IE W AR T I C LE

doi:10.1017/S1461145709990344
THEMATIC SECTION
New Aspects in the
Efficacy of modern antipsychotics in Treatment of
Affective Disorders
placebo-controlled trials in bipolar depression:
a meta-analysis
Nuria Cruz1,2, Jose Sanchez-Moreno3,4, Ferran Torres5, Jose Manuel Goikolea1,

Marc Valentı́3 and Eduard Vieta1,2
1
Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
2
International Consortium for Bipolar Disorders Research, McLean Hospital, Harvard Medical School, Boston, MA, USA
Downloaded from https://academic.oup.com/ijnp/article-abstract/13/1/5/647500 by guest on 16 October 2018

3
Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain
4
Department of Psychiatry, Universidad Autonoma de Madrid, Spain
5
Laboratory of Biostatistics & Epidemiology (Universitat Autonoma de Barcelona), Clinical Pharmacology Service,
IDIBAPS (Hospital Clinic), Barcelona, Spain
Abstract
Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the
treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar
disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern
atypical antipsychotics in bipolar depression. We systematically reviewed published or registered
randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I
and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the
Montgomery–Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined
through meta-analysis using risk ratio as an effect size with a 95 % confidence interval (95 % CI) and with a
level of statistical significance of 5 % (p<0.05). We identified five RCTs ; four involved antipsychotic
monotherapy and one addressed both monotherapy and combination with an antidepressant. The two
quetiapine trials analysed the safety and efficacy of two doses : 300 and 600 mg/d. The only olanzapine
trial assessed olanzapine monotherapy within a range of 5–20 mg/d and olanzapine–fluoxetine combi-
nation within a range of 5–20 mg/d and 6–12 mg/d, respectively. The two aripiprazole placebo-controlled
trials assessed doses of 5–30 mg/d. Quetiapine and olanzapine trials (3/5, 60 %) demonstrated superiority
over placebo (p<0.001). Only 2/5 (40 %) (both aripiprazole trials) failed in the primary efficacy measure
after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy
in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature
of atypical antipsychotics in bipolar depression.
Received 28 October 2008 ; Reviewed 16 December 2008 ; Revised 15 June 2009 ; Accepted 26 June 2009 ;
First published online 29 July 2009
Key words : Antipsychotic drugs, bipolar disorder, depression, placebo-controlled trials.
Introduction as monotherapy or adjunctive treatment (Bowden et al.

2005 ; Garcia-Amador et al. 2006 ; Hirschfeld et al. 2004 ;
Randomized, placebo-controlled trials (RCTs) have
Keck et al. 2003a, b ; Khanna et al. 2005 ; McIntyre et al.
demonstrated efficacy for atypical antipsychotics in
2005 ; Potkin et al. 2005 ; Sachs et al. 2002, 2004, 2006 ;
the treatment of acute mania in bipolar disorder, either
Smulevich et al. 2005 ; Tohen et al. 1999, 2000, 2002,
2008 ; Vieta et al. 2008b, in press ; Weisler et al. 2003 ;
Address for correspondence : E. Vieta, M.D., Ph.D., Director Bipolar Yatham et al. 2003, 2007). Currently available data
Disorders Program, Clinical Institute of Neuroscience,
suggest that combining atypical antipsychotics and
Hospital Clinic, University of Barcelona, Villarroel 170,
08036 Barcelona, Spain.
mood stabilizers is the most efficacious treatment in
Tel. : +34-93-227-5477 Fax : +34-93-227-5477 acute mania, reinforced after a systematic review and
Email : evieta@clinic.ub.es or evieta@mclean.harvard.edu meta-analysis of pooled data conducted by Perlis and
6 N. Cruz et al.
Scherk (Perlis et al. 2006 ; Scherk et al. 2007). Atypical September 2004 (aripiprazole, asenapine, clozapine,
antipsychotics have not traditionally been considered paliperidone, quetiapine, risperidone, ziprasidone,
as a major option in depression guidelines, unless olanzapine) and also amisulpiride, licensed in other
psychotic features were present during the acute de- countries, with a placebo control group. To avoid
pressive episode (APA, 2002 ; Grunze et al. 2002, 2003 ; publication bias, we checked the web (www.
Yatham et al. 2005b, 2006). Moreover, atypical anti- clinicaltrials.gov) and contacted all industry sponsors
psychotics, are generally classified as a class, despite for finalized studies. We allowed both monotherapy
their marked differences in pharmacodynamic proper- studies and studies in which the drug was in combi-
ties (D2, 5-HT, H1, a receptor affinities) (Brugue & nation with antidepressants, but only trials dealing
Vieta, 2007). Based on data from the latest studies and with bipolar depression were included.
RCTs conducted in bipolar depression, atypical anti-
psychotics do not seem to induce depressive episodes
Data analysis
as anti-manic agents, while evidence suggests some

atypical antipsychotics may have antidepressant The primary outcome in all the trials was change
(Yatham et al. 2005a) and stabilizing effects (Vieta et al. from baseline in Montgomery–Asberg Depression
2008a). Rating Scale (MADRS) score at 8 wk and this was also
In recent years, a number of placebo-controlled our criterion. The difference in change scores between
RCTs have been conducted. Meta-analytical pro- each drug and its corresponding placebo arm was
cedures allow us to answer questions about overall computed. That is, how much more improvement was
magnitude of effect and relative effect by week with observed in the drug arm compared to the placebo
greater statistical power than individual trials. Despite arm. Where standard deviations (S.D.) for change
depression being considered the hallmark of bipolar scores were not available, the median S.D. from those
disorder (Calabrese et al. 2001) and also a leading trials where S.D. was reported was used.
cause of disability and mortality (Mitchell & Malhi, We also examined outcomes by response rates,
2004), meta-analyses addressing the efficacy and defined as the proportion of subjects achieving o50 %
effectiveness of atypical antipsychotics in bipolar de- improvement, and remission rates defined as the
pression are lacking. Therefore, we conducted the first proportion of subjects achieving MADRS f12 at an
structured review and meta-analysis of randomized, endpoint. These endpoint definitions were homo-
placebo-controlled trials of atypical antipsychotics as geneous in all trials.
monotherapy for the acute treatment of depression in The between-treatment comparisons were esti-
bipolar I and/or II disorder. mated by means of the odds ratio (OR) and 95 % con-
fidence intervals (95 % CI) for the binary variables
(remission and response) and the mean difference and
Method 95 % CI for the MADRS. Since it was considered likely
a priori that not all trials would produce exactly equal
Search strategy underlying effect sizes, a random-effects model was
Studies were identified using searches of PubMed/ considered preferable to a fixed-effects models. The
Medline with the search terms ‘depression ’, ‘placebo ’, random-effects model incorporates both within-study
and each of the atypical antipsychotics, limited to and between-study variance into the estimate of aver-
randomized, controlled clinical trials ; review of ab- age treatment effects and is therefore usually more
stracts from the 2003 meetings onward of the American realistic that the fixed-effects model. We also per-
College of Neuropsychiatry, American Psychiatric formed a sensitivity analysis to assess the source of
Association, and International Conference on Bipolar heterogeneity by excluding the aripiprazole studies,
Disorder ; and consultations with study investigators as they were negative on the primary outcome. In the
and representatives of pharmaceutical companies that only olanzapine trial which included an olanzapine–
market atypical antipsychotics. The search included fluoxetine combination (OFC) treatment, we only
the period 1994–2007. considered the olanzapine monotherapy arm for the
analysis in order to obtain homogeneous compara-
tive results. The analysis was performed using SAS
Study characteristics
version 9.1.3 software (SAS Institute Inc., USA) and
We selected for inclusion randomized, controlled R software version 2.7.0 (R Development Core Team,
atypical antipsychotics approved for any indication Austria). The level of significance was established at
by the U.S. Food and Drug Administration since the 0.05 level (two-sided).
Efficacy of antipsychotics in bipolar depression 7
Table 1. Atypical antipsychotics in the treatment of bipolar depression : placebo-controlled, randomized, monotherapy
and combination therapy studies
Baseline MADRS change

Duration Patients MADRS from baseline
Study (wk) Comparators (n)a score at 8 wk
Monotherapy trials
Calabrese et al. (2005) 8 Quetiapine (300 mg) 170 30.3 x16.7
8 Quetiapine (600 mg) 172 30.4 x16.4
8 Placebo 169 30.6 x10.3
Thase et al. (2006) 8 Quetiapine (300 mg) 155 29.9 x16.0
8 Quetiapine (600 mg) 161 31.1 x16.9

8 Placebo 151 29.6 x11.9
Thase et al. (2008) 8 Aripiprazoleb 177 29.1 x12.0
(CN138096) 8 Placebo 164 28.5 x11.4
Thase et al. (2008) 8 Aripiprazoleb 176 29.56 x12.3
(CN138146) 8 Placebo 178 29.35 x11.8
Combination trials
Tohen et al. (2003) 8 Olanzapine 377 32.6 x18.5
8 OFC 370 30.8 x11.9
8 Placebo 86 31.3 x5.19
MADRS, Montgomery–Asberg Depression Rating Scale ; OFC, Olanzapine–fluoxetine combination.

a
Number of patients used in efficacy analyses.
b
Range 5–30 mg.
Results included not only the primary variable at endpoint,

but also pooled data by week, in order to assess speed
The Medline search identified 15 studies. Only three
of action. The aripiprazole trials (Thase et al. 2008) ex-
of these met the inclusion criteria. Two additional
cluded patients with psychotic features and bipolar II
studies were identified from a review of meeting pro-
patients were only enrolled in the quetiapine studies
ceedings or consultation with study investigators.
(32–34 %) ; no trials excluded patients with rapid cyc-
Quetiapine (Calabrese et al. 2005 ; Thase et al. 2006) and
ling, which represented 18–40 % of patients in the
aripiprazole, reporting two studies in one publication
studies reporting such data (Calabrese et al. 2005 ;
(Thase et al. 2008) were each tested in two trials. One
Thase et al. 2006 ; Tohen et al. 2003).
trial testing olanzapine included a combination ther-
apy (OFC) in addition to the monotherapy and the
Assessment of the MADRS scale
placebo arm (Tohen et al. 2003), No placebo-controlled
trials of amisulpride, asenapine, clozapine, paliperi- Pooled data for each antipsychotic and overall magnitude
done, risperidone or ziprasidone were identified. of effect
Random-effects estimates of each drug effect (pooled
Included studies
across all monotherapy and combination studies that
A total of five studies were included. Study charac- included that drug) and associated 95 % CIs are
teristics are given in Table 1. In general, monotherapy shown in Fig. 1 h. All quetiapine and olanzapine trials
trials were of similar size and design, with the excep- demonstrated significant superiority over placebo at
tion of the olanzapine trial, which was larger. week 8 (i.e. all CIs in the pooled analysis excluded
Assessment of depressive symptoms was performed zero). The overall mean estimate was x3.91 (95 % CI
using the MADRS as a primary variable in all trials. x5.55 to x2.26, p<0.001). Treatment effects exhi-
The baseline depression scores were similar in all bited a high degree of heterogeneity on the global
the studies with moderate to severely depressed assessment (p=0.013). However, when assessing
patients at inclusion (score range from 28.49 to 32.6). the estimates within each drug, the heterogeneity
The duration of all studies was 8 wk. The analysis was substantially reduced [quetiapine : p=0.803 ;
8 N. Cruz et al.
(a) (b)
Study Estimates with 95% confidence intervals Study Estimates with 95% confidence intervals
Quetiapine Quetiapine
Calabrese (2005), Quetiapine 600 mg Calabrese (2005), Quetiapine 600 mg
Thase (2006), Quetiapine 600 mg Thase (2006), Quetiapine 600 mg
Pooled –3.47 (–4.53 to –2.42) Pooled –4.32 (–5.52 to –3.11)
Olanzapine Olanzapine
Tohen (2003), Olanzapine 5–20 mg Tohen (2003), Olanzapine 5–20 mg
Aripiprazole Aripiprazole
Thase (2008) (CN138096), Aripiprazole 5–30 mg Thase (2008) (CN138096), Aripiprazole 5–30 mg
Pooled (random effects) –2.88 (–3.57 to –2.19) Pooled (random effects) –3.47 (–4.28 to –2.66)
–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 –12 –10 –8 –6 –4 –2 0 1 2 3 4 5

Absolute baseline reduction Absolute baseline reduction
Active better Control better Active better Control better
(c) (d)
–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 –12 –10 –8 –6 –4 –2 0 1 2 3 4 5

(e) (f )
–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 –12 –10 –8 –6 –4 –2 0 1 2 3 4 5

Fig. 1. For legend see next page.
olanzapine : p non-estimable (one study) ; aripiprazole : Pooled data for each antipsychotic by week
p=0.813]. Moreover, when performing the sensi-
tivity analysis excluding the aripiprazole group, the All of the atypical antipsychotics demonstrated sig-
heterogeneity was then negligible (p=0.302), and the nificant efficacy from week 1 and throughout the
pooled mean was x4.90 (95 % CI x6.21 to x3.59, first 6 wk, which was the time with the maximal effect
p<0.001) (see Fig. 2). size reported by all of the studies. From week 6 to
(g) (h)

–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 –12 –10 –8 –6 –4 –2 0 1 2 3 4 5
Fig. 1. Random-effects estimates and associated 95 % confidence intervals for active vs. placebo effect in
Montgomery–Asberg Depression Rating Scale (MADRS) for quetiapine, olanzapine, and aripiprazole at (a) week 1,
(b) week 2, (c) week 3, (d) week 4, (e) week 5, (f) week 6, (g) week 7, (h) week 8.
Treatment effects regarding response exhibited a

Study Estimates with 95% confidence intervals
high degree of heterogeneity on the global assessment
Quetiapine
Calabrese (2005), Quetiapine 600 mg (p=0.018). However, when assessing the estimates
Calabrese (2005), Quetiapine 300 mg within each drug, the heterogeneity was substan-
Thase (2006), Quetiapine 600 mg
tially reduced [quetiapine : p=0.266 ; olanzapine :
Thase (2006), Quetiapine 300 mg
Pooled –5.63 (–7.05 to –4.21) p non-estimable (one study) ; aripiprazole : p=0.5930].
Olanzapine
Further, when performing the sensitivity analysis
Tohen (2003), Olanzapine 5–20 mg excluding the aripiprazole group, the heterogeneity
Pooled –3.10 (–5.18 to –1.02) was smaller (p=0.1280), and the pooled OR was 0.55
Pooled (random effects) –4.90 (–6.21 to –3.59) (95 % CI 0.41–0.74, p<0.001) (see Fig. 3 b).
–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 Remission (overall magnitude for all antipsychotics)

Absolute baseline reduction
Active better Control better Proportion of patients achieving a clinical remission,
defined as the proportion of subjects achieving
Fig. 2. Random-effects estimates of quetiapine and
MADRS f12 at endpoint, were reported for all trials
olanzapine and associated 95 % confidence intervals for
by active vs. placebo effect. Random-effects analysis
active vs. placebo effect in Montgomery–Asberg Depression
Rating Scale (MADRS) at week 8. The aripiprazole group
were pooled, estimated with an overall effect size of
was excluded from the analysis. 0.67 (95 % CI 0.45–0.98) (see Fig. 4 a).
Treatment effects regarding remission also showed
a high degree of heterogeneity on global assessment
endpoint quetiapine and olanzapine maintained their (p=0.0010). However, when assessing the estimates
superiority over placebo, but aripiprazole did not within each drug, the heterogeneity was substantially
(see Fig. 1). reduced [quetiapine : p=0.119 ; olanzapine : p non-
estimable (one study) ; aripiprazole : p=0.415].
Assessment of response and remission Moreover, when performing the sensitivity analysis
Response (overall magnitude for all antipsychotics) excluding the aripiprazole group, the heterogeneity
was smaller (p=0.052), and the pooled OR was 0.51
The proportion of patients achieving a clinical re- (95 % CI 0.35–0.74, p<0.001) (see Fig. 4 b).
sponse, defined as a 50 % reduction in MADRS score
from baseline to endpoint, were reported for all trials
Discussion
by active vs. placebo effect. Random-effects analysis
were pooled, estimated with an overall effect size (OR To our knowledge, this is the first meta-analysis ad-
0.66, 95 % CI 0.49–0.89) (see Fig. 3a). dressing the efficacy of atypical antipsychotics in the
10 N. Cruz et al.
(a) (b)
Quetiapine
Quetiapine
Calabrese (2005), Quetiapine 300 and 600 mg
Thase (2006), Quetiapine 300 and 600 mg Calabrese (2005), Quetiapine 300 and 600 mg
Pooled 0.48 (0.35 to 0.65) Thase (2006), Quetiapine 300 and 600 mg
Olanzapine 0.48 (0.35 to 0.65)
Pooled
Tohen (2003), Olanzapine range 5–20 mg
Pooled 0.68 (0.50 to 0.93)
Olanzapine
Aripiprazole Tohen (2003), Olanzapine range 5–20 mg
Thase (2008) (CN138096), Aripiprazole range 5–30 mg
Thase (2008) (CN138146), Aripiprazole 5–30 mg Pooled 0.68 (0.50 to 0.93)
Pooled 0.93 (0.69 to 1.25)
Pooled (random effects) 0.55 (0.41 to 0.74)
Pooled (random effects) 0.66 (0.49 to 0.89)
0.1 0.3 1.0 3.0 10.0 0.1 0.3 1.0 3.0 10.0

Odds ratio Odds ratio
Active better Placebo better Active better Placebo better
Fig. 3. (a) Random-effects estimates of quetiapine, olanzapine, and aripiprazole and associated 95 % confidence intervals
for active vs. placebo effect in response rates. (b) Random-effects estimates excluding the aripiprazole group.
(a) (b)
Quetiapine
Calabrese (2005), Quetiapine 300 and 600 mg Quetiapine
Thase (2006), Quetiapine 300 and 600 mg Calabrese (2005), Quetiapine 300 and 600 mg
Pooled 0.44 (0.29 to 0.68)
Thase (2006), Quetiapine 300 and 600 mg
Olanzapine
Pooled 0.44 (0.29 to 0.68)
Pooled 0.67 (0.48 to 0.93)
Olanzapine
Aripiprazole
Thase (2008) (CN138096), Aripiprazole 5–30 mg
Thase (2008) (CN138146), Aripiprazole 5–30 mg Pooled 0.67 (0.48 to 0.93)
Pooled 1.05 (0.75 to 1.46)
Pooled (random effects) 0.67 (0.45 to 0.98) Pooled (random effects) 0.51 (0.35 to 0.74)
0.1 0.3 1.0 3.0 10.0 0.1 0.3 1.0 3.0 10.0
Odds ratio Odds ratio
Active better Placebo better Active better Placebo better
Fig. 4. (a) Random-effects estimates of quetiapine, olanzapine, and aripiprazole and associated 95 % confidence intervals
for active vs. placebo effect in remission rates. (b) Random-effects estimates excluding the aripiprazole group.
treatment of bipolar depression. Its results suggest antidepressant and mood-stabilizing agents, which
that some second-generation antipsychotics (quetia- are still mentioned as first-line treatments for bipolar
pine and olanzapine) may additionally represent a depression (Yatham et al. 2005a, 2006). Of course,
monotherapy management option of bipolar I and/or guidelines and clinicians not only look into efficacy,
II depression. Bipolar disorders present initially with but also safety and tolerability as well when prioritiz-
a depressive episode in >50 % of patients, which is ing treatment options, but it is likely that future
considered the major burden of bipolar disorder updates of the major guidelines may shift upwards
in terms of disability and suicide risk (Colom et al. atypical antipsychotics in bipolar depression in their
2006 ; Daban et al. 2006 ; Mitchell et al. 2008). Currently, suggested algorithms.
atypical antipsychotics are only considered by treat- We found some atypical antipsychotics (quetiapine
ment guidelines as second- or third-line therapy in and olanzapine) as monotherapy were significantly
the management of bipolar depression (Fountoulakis more efficacious than placebo (Calabrese et al. 2005 ;
et al. 2007), despite the dearth of positive placebo- Thase et al. 2006 ; Tohen et al. 2003), as indicated by
controlled trials with alternative compounds, such greater reductions in MADRS scores, in the treatment
as lithium, lamotrigine or various combinations of of acute bipolar depression from week 1 onwards,
except for aripiprazole trials which have shown a 6-wk akathisia perhaps related to dosing), leading to
limited superiority compared to placebo, decreasing drop-outs and also related to differences in its mech-
its effect size at endpoint (Thase et al. 2008). anism of action such as too high D2 affinity and low
The very early onset of action of all tested atypical H1 affinity compared to quetiapine and olanzapine.
antipsychotics in the treatment of bipolar depression, The studies also differed in whether they included
even as monotherapy, may highlight an overlapping rapid-cycling patients or those in mixed states and
mechanism of action of these drugs as a potential also in the proportion of bipolar I or II patients with
class effect with independence of the monoaminergic psychotic features. However, the exploratory analyses
pathways. reported to date suggest little or no difference in
The relevant question of whether initial combi- overall efficacy across these subgroups. Overall, bi-
nation therapy with a mood stabilizer is superior polar II and rapid-cycling patients highlight lower
to monotherapy with an atypical antipsychotic thus effect sizes in primary outcome, although with sig-
cannot be answered with the present available data. nificantly superiority to placebo group in the treat-

The superiority of quetiapine and olanzapine mono- ment of bipolar depression. Moreover, the incidence
therapy by week is emphasized by higher response of treatment-emergent mania was low (from 3.6 % for
and remission rates and, except for aripiprazole, lower higher quetiapine doses to a maximum of 5.7 % for
drop-out rates due to adverse events. Overall, com- olanzapine trials) and not significantly different from
pletion rates were homogeneous with an average of placebo for any drug.
y60 % for patients under quetiapine and OFC and Regarding tolerability, quetiapine was generally
slightly less for olanzapine monotherapy and aripi- safe and well tolerated in both tested doses. The most
prazole treatment groups. common adverse effects reported in y30 % of patients
We elected to compare drugs based upon their dif- were not severe, mostly somnolence and sedation
ference from placebo, rather than absolute change in leading to withdrawal from the study, with most
MADRS score, as a means of controlling for study discontinuations occurring within the first week.
differences. Importantly, changes in weight observed in all three
Remission is often considered the most clinically groups were relatively small and did not result in
useful endpoint, defined as an almost complete ab- withdrawal from the study. In fact, weight gain as-
sence of mood symptoms, which in our meta-analysis sociated to quetiapine administration was mild and
represented a proportion of patients achieving a dose-related, with <9 % of patients gaining o7 %
MADRS score of f12. We obtained significant pro- from baseline as a clinical meaningfully measurement.
gressive superiority throughout the first 6 wk for all The olanzapine adverse-event profile was consist-
drugs, which was maintained to an endpoint only ent with previously reported findings whereas the
by quetiapine and olanzapine. OFC profile was similar to that of olanzapine, except
The homogeneity across the trials’ design and also for higher rates of nausea and diarrhoea. Small but
in their study sample characteristics were the rule. statistically significant mean increases in glucose and
Severity of depression at baseline did not show sub- cholesterol levels were also seen. Patients under olan-
stantial differences and placebo response between zapine treatment reported, as expected, about an 18 %
studies was surprisingly highly homogeneous and significant weight gain compared to the placebo
may be not considered as a source of heterogeneity. arm. Nevertheless, only 9 % of patients dropped out
The heterogeneity in this meta-analysis was due to a in olanzapine trials due to overall adverse events.
differential effect in the aripiprazole group compared The high rates of drop-outs had been related to
to the olanzapine and quetiapine groups, but not due aripiprazole trials (study 1, 46.8 % vs. 35.1 % in placebo
to intra-treatment heterogeneity. Therefore, in our re- arm and study 2, 41.2 % vs. 29.8 %, respectively),
sults, aripiprazole may be considered an important and they were more associated to intolerable adverse
single source of heterogeneity, therefore there were events, especially akathisia. No meaningfully clinical
no relevant differences in design among the bipolar changes on weight were reported
depression studies or in dosage used for the same Regarding limitations, there were very few studies
drugs. available that currently met the inclusion criteria.
It should be taken into account that we studied Moreover, the studies included in that meta-analysis
higher aripiprazole doses as a monotherapy compared were not adequately powered to detect differences
to its use in combination with mood stabilizers. This in subpopulations of bipolar depression to allow us to
fact suggests one potential reason for failed results in perform subanalysis for bipolar II subtype. Never-
the aripiprazole trials (tolerability issues, especially theless, exploratory analysis performed in quetiapine
12 N. Cruz et al.
trials exerts quite qualitative homogeneous results Eli-Lilly, Forest Research Institute, GlaxoSmithKline,
for this subpopulation (Suppes et al. 2008). Further Janssen, Jazz, Lundbeck, Novartis, Organon, Otsuka,
analyses of the pooled data are needed to examine Pfizer, Sanofi-Aventis, Servier, and UBC. J. M.
the therapeutic effect with regard to other clinically Goikolea has been a member of the speakers’ boards
relevant factors such chronicity, sex, history of suicide for Bristol–Myers Squibb, Eli-Lilly, GlaxoSmithKline,
attempts or substance abuse. Otsuka, and Sanofi-Aventis ; and has served as a con-
Moreover adjunctive studies with mood stabilizers sultant for AstraZeneca and Bristol–Myers Squibb.
are needed to compare the benefit–risk ratio and also
to conduct more placebo-controlled studies of main-
References
tenance of antidepressant effect of atypical antipsy-
chotic as monotherapy. APA (2002). Practice guidelines for the treatment of patients
In summary our results suggest some atypical anti- with bipolar disorder (revision). American Journal of
psychotics (quetiapine and olanzapine) may be con- Psychiatry 159, 1–50.

sidered as a first-line management option in acute Bowden CL, Grunze H, Mullen J, Brecher M, et al. (2005).
A randomized, double-blind, placebo-controlled efficacy
bipolar I and/or II depression, even for poor re-
and safety study of quetiapine or lithium as
sponder subgroups such as rapid cyclers and patients
monotherapy for mania in bipolar disorder. Journal
with psychotic features. The question of their class
of Clinical Psychiatry 66, 111–121.
effect seems to be answered positively regarding Brugue E, Vieta E (2007). Atypical antipsychotics in bipolar
its early onset of action but with differences in the depression : Neurobiological basis and clinical
magnitude and maintenance of effect. These results implications. Progress in Neuropsychopharmacology and
raise questions on the current approach by most Biological Psychiatry 31, 275–282.
treatment guidelines and on the potential mechanism Calabrese JR, Keck Jr. PE, Macfadden W, Minkwitz M,
of the action involved in the improvement of de- et al. (2005). A randomized, double-blind,
pressive symptoms in bipolar depression by means of placebo-controlled trial of quetiapine in the treatment
drugs traditionally considered as antipsychotics. of bipolar i or ii depression. American Journal of Psychiatry
162, 1351–1360.
Calabrese JR, Shelton MD, Bowden CL, Rapport DJ,
Acknowledgements et al. (2001). Bipolar rapid cycling : focus on depression
as its hallmark. Journal of Clinical Psychiatry 62 (Suppl. 14),
We thank the following pharmaceutical companies : 34–41.
AstraZeneca, Bristol–Myers Squibb and Eli-Lilly, for Colom F, Vieta E, Daban C, Pacchiarotti I,
kindly providing us with all the requested data for the Sanchez-Moreno J (2006). Clinical and therapeutic
analysis. This project was funded by the CIBERSAM implications of predominant polarity in bipolar disorder.
(Centro de Investigación Biomédica en Red de Salud Journal of Affective Disorders 93, 13–17.
Mental, CB07/07/0004) from the Spanish Ministry of Daban C, Colom F, Sanchez-Moreno J, Garcia-Amador M,
Science and Innovation. N.C. is funded by the Spanish Vieta E (2006). Clinical correlates of first-episode
polarity in bipolar disorder. Comprehensive Psychiatry 47,
Ministry of Science and Innovation, Instituto Carlos III
433–437.
through a ‘ Rio Hortega ’ contract.
Fountoulakis KN, Vieta E, Siamouli M, Valenti M, et al.
(2007). Treatment of bipolar disorder : a complex
Statement of Interest treatment for a multi-facet disorder. Annals of General
Psychiatry 6, 27.
E. Vieta has received grant/research support from Garcia-Amador M, Pacchiaroti I, Valenti M, Sanchez RF,
Almirall, AstraZeneca, Bristol–Myers Squibb, Eli-Lilly, et al. (2006). Role of aripiprazole in treating mood
the European 7th Framework Program, GlaxoSmith- disorders. Expert Review of Neurotherapeutics 6,
Kline, Janssen-Cilag, Novartis, Organon, Otsuka, 1777–1783.
Pfizer, Sanofi-Aventis, Seny Foundation, Servier, the Grunze H, Kasper S, Goodwin G, Bowden C, et al. (2002).
World Federation of Societies of Biological Psychiatry
Spanish Ministry of Health (CIBERSAM), the Spanish
(WFSBP) Guidelines for Biological Treatment of Bipolar
Ministry of Science and Education, and the Stanley
Disorders. Part I : Treatment of bipolar depression. World
Medical Research Institute ; has been a member of
Journal of Biological Psychiatry 3, 115–124.
the speakers’ boards for Almirall, AstraZeneca, Grunze H, Kasper S, Goodwin G, Bowden C, et al. (2003).
Bristol–Myers Squibb, Eli Lilly, Esteve, GlaxoSmith- The World Federation of Societies of Biological Psychiatry
Kline, Janssen, Lundbeck, Novartis, Organon, Otsuka, (WFSBP) Guidelines for the Biological Treatment of
Pfizer, Sanofi-Aventis, and Servier ; and has served as Bipolar Disorders, Part II : Treatment of Mania. World
a consultant for AstraZeneca, Bristol-Myers Squibb, Journal of Biological Psychiatry 4, 5–13.
Hirschfeld RM, Keck Jr. PE, Kramer M, Karcher K, et al. in bipolar mania : a 3-week placebo-controlled trial
(2004). Rapid antimanic effect of risperidone followed by a 9-week double-blind trial of risperidone
monotherapy : a 3-week multicenter, double-blind, and haloperidol. European Neuropsychopharmacology 15,
placebo-controlled trial. American of Journal Psychiatry 161, 75–84.
1057–1065. Suppes T, Hirschfeld RM, Vieta E, Raines S, Paulsson B
Keck Jr. PE, Marcus R, Tourkodimitris S, Ali M, et al. (2008). Quetiapine for the treatment of bipolar II
(2003a). A placebo-controlled, double-blind study of the depression : analysis of data from two randomized,
efficacy and safety of aripiprazole in patients with acute double-blind, placebo-controlled studies. World Journal
bipolar mania. American of Journal Psychiatry 160, of Biological Psychiatry 9, 198–211.
1651–1658. Thase ME, Jonas A, Khan A, Bowden CL, et al. (2008).
Keck Jr. PE, Versiani M, Potkin S, West SA, et al. (2003b). Aripiprazole monotherapy in nonpsychotic bipolar I
Ziprasidone in the treatment of acute bipolar mania : depression : results of 2 randomized, placebo-controlled
a three-week, placebo-controlled, double-blind, randomized studies. Journal of Clinical Psychopharmacology 28, 13–20.
trial. American of Journal Psychiatry 160, 741–748. Thase ME, Macfadden W, Weisler RH, Chang W, et al.

Khanna S, Vieta E, Lyons B, Grossman F, et al. (2005). (2006). Efficacy of quetiapine monotherapy in bipolar I
Risperidone in the treatment of acute mania : Double-blind, and II depression : a double-blind, placebo-controlled
placebo-controlled study. British of Journal Psychiatry 187, study (the BOLDER II study). Journal of Clinical
229–234. Psychopharmacology 26, 600–609.
McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J Tohen M, Bowden CL, Smulevich AB, Bergstrom R, et al.
(2005). Quetiapine or haloperidol as monotherapy for (2008). Olanzapine plus carbamazepine v. carbamazepine
bipolar mania – a 12-week, double-blind, randomised, alone in treating manic episodes. British Journal of
parallel-group, placebo-controlled trial. European Psychiatry 192, 135–143.
Neuropsychopharmacology 15, 573–585. Tohen M, Chengappa KN, Suppes T, Zarate Jr. CA, et al.
Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RM (2002). Efficacy of olanzapine in combination
(2008). Diagnostic guidelines for bipolar depression : with valproate or lithium in the treatment of mania
a probabilistic approach. Bipolar Disorders 10, 144–152. in patients partially nonresponsive to valproate or
Mitchell PB, Malhi GS (2004). Bipolar depression : lithium monotherapy. Archives of General Psychiatry 59,
phenomenological overview and clinical characteristics. 62–69.
Bipolar Disorders 6, 530–539. Tohen M, Jacobs TG, Grundy SL, McElroy SL, et al.
Perlis RH, Welge JA, Vornik LA, Hirschfeld RM, Keck Jr. (2000). Efficacy of olanzapine in acute bipolar mania :
PE (2006). Atypical antipsychotics in the treatment of a double-blind, placebo-controlled study. The Olanzipine
mania : a meta-analysis of randomized, placebo-controlled HGGW Study Group. Archives of General Psychiatry 57,
trials. Journal of Clinical Psychiatry 67, 509–516. 841–849.
Potkin SG, Keck Jr. PE, Segal S, Ice K, English P (2005). Tohen M, Sanger TM, McElroy SL, Tollefson GD, et al.
Ziprasidone in acute bipolar mania : a 21-day randomized, (1999). Olanzapine versus placebo in the treatment of acute
double-blind, placebo-controlled replication trial. Journal mania. Olanzapine HGEH Study Group. American of
of Clinical Psychopharmacology 25, 301–310. Journal Psychiatry 156, 702–709.
Sachs G, Chengappa KN, Suppes T, Mullen JA, et al. Tohen M, Vieta E, Calabrese J, Ketter TA, et al. (2003).
(2004). Quetiapine with lithium or divalproex for the Efficacy of olanzapine and olanzapine-fluoxetine
treatment of bipolar mania : a randomized, double-blind, combination in the treatment of bipolar I depression.
placebo-controlled study. Bipolar Disorders 6, 213–223. Archives of General Psychiatry 60, 1079–1088.
Sachs G, Sanchez R, Marcus R, Stock E, et al. (2006). Vieta E, Ramey T, Keller D, English PA, et al. (in press).
Aripiprazole in the treatment of acute manic or mixed Ziprasidone in the treatment of acute mania : a 12-week
episodes in patients with bipolar I disorder : a 3-week placebo-controlled, haloperidol-referenced study. Journal
placebo-controlled study. Journal of Psychopharmacology of Psychopharmacology.
20, 536–546. Vieta E, Suppes T, Eggens I, Persson I, et al. (2008 a).
Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Efficacy and safety of quetiapine in combination with
Bowden CL (2002). Combination of a mood stabilizer lithium or divalproex for maintenance of patients with
with risperidone or haloperidol for treatment of acute bipolar I disorder (international trial 126). Journal of
mania : a double-blind, placebo-controlled comparison of Affective Disorders 109, 251–263.
efficacy and safety. American of Journal Psychiatry 159, Vieta E, T’joen C, McQuade RD, Carson Jr. WH, et al.
1146–1154. (2008b). Efficacy of adjunctive aripiprazole to either
Scherk H, Pajonk FG, Leucht S (2007). Second-generation valproate or lithium in bipolar mania patients partially
antipsychotic agents in the treatment of acute mania : nonresponsive to valproate/lithium monotherapy : a
a systematic review and meta-analysis of randomized placebo-controlled study. American Journal of Psychiatry
controlled trials. Archives of General Psychiatry 64, 442–455. 165, 1316–1325.
Smulevich AB, Khanna S, Eerdekens M, Karcher K, et al. Weisler R, Dunn J, English P (2003). Adjunctive ziprasidone
(2005). Acute and continuation risperidone monotherapy for acute bipolar mania : randomized, placebo-controlled
14 N. Cruz et al.
trial. 4th International Forum on Mood and Anxiety management of patients with bipolar disorder :
Disorders, Monte Carlo, Monaco. consensus and controversies. Bipolar Disorders 7 (Suppl. 3),
Yatham LN, Goldstein JM, Vieta E, Bowden CL, et al. 5–69.
(2005a). Atypical antipsychotics in bipolar depression : Yatham LN, Kennedy SH, O’Donovan C, Parikh SV,
potential mechanisms of action. Journal of Clinical et al. (2006). Canadian Network for Mood and Anxiety
Psychiatry 66 (Suppl. 5), 40–48. Treatments (CANMAT) guidelines for the management
Yatham LN, Grossman F, Augustyns I, Vieta E, of patients with bipolar disorder : update 2007. Bipolar
Ravindran A (2003). Mood stabilisers plus risperidone or Disorders 8, 721–739.
placebo in the treatment of acute mania. International, Yatham LN, Vieta E, Young AH, Moller HJ, Paulsson B,
double-blind, randomised controlled trial. British of Vagero M (2007). A double blind, randomized,
Journal Psychiatry 182, 141–147. placebo-controlled trial of quetiapine as an add-on
Yatham LN, Kennedy SH, O’Donovan C, Parikh S, et al. therapy to lithium or divalproex for the treatment of
(2005b). Canadian Network for Mood and Anxiety bipolar mania. International Clinical Psychopharmacology
Treatments (CANMAT) guidelines for the 22, 212–220.

E Cacy of Modern Antipsychotics in Placebo-Controlled Trials in Bipolar Depression: A Meta-Analysis

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International Journal of Neuropsychopharmacology (2010), 13, 5–14.

Copyright f CINP 2009 R E V IE W AR T I C LE

Nuria Cruz1,2, Jose Sanchez-Moreno3,4, Ferran Torres5, Jose Manuel Goikolea1,

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Introduction as monotherapy or adjunctive treatment (Bowden et al.

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Baseline MADRS change

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MADRS, Montgomery–Asberg Depression Rating Scale ; OFC, Olanzapine–ﬂuoxetine combination.

Results included not only the primary variable at endpoint,

–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 –12 –10 –8 –6 –4 –2 0 1 2 3 4 5

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–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 –12 –10 –8 –6 –4 –2 0 1 2 3 4 5

–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 –12 –10 –8 –6 –4 –2 0 1 2 3 4 5

Fig. 1. For legend see next page.

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Treatment eﬀects regarding response exhibited a

–12 –10 –8 –6 –4 –2 0 1 2 3 4 5 Remission (overall magnitude for all antipsychotics)

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