International Journal of Neuropsychopharmacology (2013), 16, 1719–1732.
doi:10.1017/S1461145713000278
© CINP 2013
ARTICLE
Clinical management and burden of bipolar
disorder: results from a multinational
longitudinal study (WAVE-bd)
Eduard Vieta1, Jens M. Langosch2, Maria Luisa Figueira3, Daniel Souery4,
Elena Blasco-Colmenares5, Esteban Medina6, Miriam Moreno-Manzanaro6,
Miguel Angel Gonzalez7 and Frank Bellivier8
1
Bipolar Disorders Program, Hospital Clínic, University of Barcelona, Barcelona, Spain
Bethanien Hospital for Psychiatry, Psychosomatics, and Psychotherapy, Greifswald, Germany
3
Psychiatric Department, Hospital Santa Maria, Faculty of Medicine, University of Lisbon, Portugal
4
Centre Européen de Psychologie Médicale/Psy-Pluriel, Brussels, Belgium
5
Johns Hopkins University Institution, SOM DOM Cardiology, MD, USA
6
Medical Department, AstraZeneca Pharmaceuticals, Madrid, Spain
7
Quintiles, Madrid, Spain
8
AP-HP, GH Saint-Louis-Lariboisière-Fernand Widal, Paris, France
2
Abstract
Bipolar disorder is a mood disorder which requires complex treatment. Current treatment guidelines
are based on the results of published randomized clinical trials and meta-analyses which may not
accurately reflect everyday clinical practice. This multi-national, multi-centre, observational cohort study
describes clinical management and clinical outcomes related to bipolar disorder in real-life settings,
assesses between-country variability and identifies factors associated with clinical outcomes. Adults
from 10 countries in Europe and South America who experienced at least one mood episode in the preceding 12 months were included. Overall, 2896 patients were included in the analyses and followed for at least
9 months across a retrospective and prospective study phase. Main outcome measures were the number
and incidence rate of mood episodes (relapses and recurrences) and healthcare resource use including
pharmacological treatments. Relapses and recurrences were reported in 18.2 and 40.5% of patients, respectively; however, the reported incidence rate of relapses was higher than that of recurrences [1.562 per
person-year (95% CI 1.465–1.664) vs. 0.691 per person-year (95% CI 0.657–0.726)]. Medication use was
high during all episode types and euthymia; the percentage of patients receiving no medication ranged
from 11.0% in mania to 6.1% in euthymia. Antipsychotics were the most commonly prescribed drug
class in all disease phases except for patients with depression, where antidepressants were more frequently
prescribed. Visits to the psychiatrist were the most frequently used healthcare resource. These results provide a description of treatment patterns for bipolar disorder across different countries and indicate factors
related to relapse and recurrence.
Received 24 October 2012; Reviewed 26 November 2012; Revised 26 February 2013; Accepted 3 March 2013;
First published online 13 May 2013
Key words: Bipolar disorder, disease management, recurrence, relapse.
Introduction
Bipolar disorder (BD) is a category of lifelong mood
disorders characterized by the presence of one or
Address for correspondence: Dr E. Vieta, Director of the Bipolar
Disorders Program, Hospital Clínic, University of Barcelona, IDIBAPS,
CIBERSAM, 170 Villarroel St., 08036, Barcelona, Spain.
Tel.: +34 932275400 Fax: +34 932279228
Email: [email protected]
more recurrent episodes of mania, depression and
mixed episodes which include both manic and
depressive symptoms. BD is estimated to have a prevalence of between 0.2 and 6%, depending on the range
of bipolar spectrum disorders included (Hakkaart
et al., 2004; Mitchell et al., 2004; Pini et al., 2005;
Baldessarini et al., 2007; Saarni et al., 2010). However,
it has been noted that complex clinical presentations
contribute to high levels of misdiagnosis of BD,
mainly as major depressive disorder; therefore,
1720 E. Vieta et al.
prevalence figures may be underestimates (Kamat
et al., 2008; Stensland et al., 2008; Ruggero et al.,
2010; Angst et al., 2011). BD has a substantial global
burden of disease; the World Health Organization
World Health Report on Mental Health acknowledged
BD as the ninth leading cause of years of ‘healthy’
life lost due to premature mortality and disability
(disability adjusted life-years) in those aged 15–44 yr
(WHO, 2012a), and in 2004, BD accounted for an estimated 0.9% of the total global burden of disease worldwide (WHO, 2012b).
Treatment of patients with BD aims to relieve
symptoms, prevent further episodes (relapses and/or
recurrences) and to recover previous psychosocial
functioning. National and international professional
organisations have published treatment guidelines
(NICE, 2006; Grunze et al., 2009, 2010, 2013; Yatham
et al., 2009; APA, 2012; Crismon et al., 2012) which
are generally in agreement regarding clinical management and pharmacological therapy. Available BD
treatment guidelines are based on the results of
published randomized clinical trials (RCTs) and
meta-analysis studies (Nivoli et al., 2011, 2012),
which provide vital evidence of efficacy when assessing novel treatments and management practices.
However, the design and structure of RCTs have
inherent limitations, when viewed in the context of
the full disease (Post, 2009). For example, RCTs generally focus on a single disease phase or treatment,
although in clinical practice most patients receive multiple drugs across different phases of the disease.
Furthermore, RCTs typically exclude patients with
severe disease or co-morbidities such as suicidal behaviour, alcohol and drug dependence, or personality
and anxiety disorders which are highly prevalent
within BD (George et al., 2003; Valtonen et al., 2005;
McIntyre et al., 2006; Swann, 2010).
The Wide AmbispectiVE study of the clinical
management and burden of BD (WAVE-bd) is a pioneering, non-interventional longitudinal study, undertaken to provide accurate and reliable information on
the management of patients with BD in conditions
representative of everyday clinical practice across
different countries in Europe and South America.
This study investigates BD from a comprehensive perspective, considering all the phases of the disease in a
global population. This allows description of the management of patients with BD across different countries,
and identification of the risk factors associated with
clinical outcomes such as recurrences and relapses.
The design of this study has been reported previously
(Vieta et al., 2011a, b). This paper presents the study
results for the first time.
Method
Study design
The study design of WAVE-bd has been described in
detail in our previously published methodology
papers (Vieta et al., 2011a, b). Briefly, WAVE-bd
(NCT01062607) is a multi-national, multi-centre, observational longitudinal study of patients diagnosed with
BD type I or type II in any phase of the disorder who
had experienced at least one mood event during the 12
months before enrolment. WAVE-bd included a retrospective and prospective phase. The retrospective
phase analysed patients’ medical information from
index episode (the first mood episode in the retrospective period, which occurred 12–3 months before study
start) to study start. The prospective phase analysed
patients’ medical information between study start
and the last visit of the last patient included in the
study. Patients spent a variable amount of time in the
study depending on the date of their index episode,
the date of patient study start, and the length of the
enrolment period; study time ranged 12–27 months.
In total, 239 sites were selected across 10 countries
(Austria, Belgium, Brazil, France, Germany, Portugal,
Romania, Turkey, Ukraine and Venezuela) to obtain
a patient population representative of everyday clinical
practice. Patients were recruited from both in-patient
and out-patient settings (mental health centres, clinics,
private settings, hospitals or specialized units) and site
selection was based on the percentage of patients that
attend different types of sites in each country (Vieta
et al., 2011a, b). Site capacity was assessed prior to
enrolment and a range of patients to be enrolled was
agreed on which would be representative, feasible
and provided the final total sample required per site
and country. Either every eligible patient identified
was invited to participate, or in sites that exceeded
the target sample size (e.g. study sites with limited
resource capacity and/or high numbers of eligible
patients during the recruitment period), a representative sample was randomly selected by electronic application (Vieta et al., 2011a, b).
Study objectives
The primary objectives of WAVE-bd were to describe
clinical management and clinical outcomes related to
BD in conditions representative of routine clinical
practice in each of the participating countries, and to
evaluate the variability between countries and the factors associated with clinical outcomes (such as patient
characteristics; country; treatment). Secondary objectives included: estimation of treatment adherence in
Clinical management and burden of BD:WAVE-bd 1721
BD and identification of patients at a higher risk of low
adherence; assessment of quality of life and functioning of patients with BD in real-life settings; assessment
of burden on caregivers; determination of healthcare
resource use; estimation of associated factors. The primary study objectives and the secondary objective of
healthcare resource use are reported in this paper.
Outcome measures
Outcome measures are summarized in Supplementary
Table S1. Clinical outcomes were evaluated using
an electronic adaptation of the National Institute of
Mental Health Life Chart Methodology and the
Clinical Global Impression for Bipolar Illness Scale (prospective phase only; Spearing et al., 1997; Denicoff
et al., 2000; Vieta et al., 2011a, b). The primary evaluation
criteria for clinical outcomes were the frequency of
mood episodes in terms of ‘syndromic’ relapses and
recurrences, and estimation of factors associated with
the number of relapses and recurrences during the
study period. Relapse was defined as a mood episode
of any polarity within 8 wk of the end of the previous
mood episode during the study period. Recurrence
was defined as a mood episode of any polarity after
8 wk from the end of the previous mood episode
during the study period. Relapses and recurrences
were identified according to the judgment of the clinician, and both included episodes of any polarity, in
accordance with Hirschfeld et al. (2007). The frequency
of suicide attempts during the study period and estimation of factors associated with the number of suicide
attempts were also assessed. Clinical management
outcomes were pharmacological treatments and nonpharmacological therapies received for BD during
the study period, as determined by patient records,
the frequency of visits to different types of healthcare
resources and estimation of factors related to
healthcare resource use.
Statistical analysis
Sample size was calculated as described previously
(Vieta et al., 2011a, b). The frequency of clinical outcomes were determined with incidence rates (IRs),
expressed in person-years. Reported IRs for relapses/
recurrences were calculated as the number of times a
relapse/recurrence occurred during follow-up (time
between the end of the study index episode and the
end of study follow-up) divided by the total time (in
years). Reported IRs (in person-years) for suicide
attempts were calculated as the number of attempts
from the onset of the study index episode to the end
of study period divided by the total time of exposure
in years.
To estimate the association of number of relapses,
recurrences or suicide attempts with individual
patient characteristics, multivariate analysis was performed. The type of model used was pre-specified as
Poisson regression (stratifying by centre), with characteristics included in the final model based on clinical
relevance and/or impact on the univariate model.
Models provided estimates of the IR ratios (IRRs) of
the response variable comparing categories of interest
adjusted for participant level covariates (country,
type of centre, demographics, medical history, disease
characteristics and characteristics of index episode).
Clinical factors with a mean IRR>1.05 [with confidence
intervals (CI) not including 1 and a p value <0.05] were
considered to be associated with a higher number of
relapses/recurrences/suicide attempts. Clinical factors
with a mean IRR<0.95 (with CI not including 1 and
a p value <0.05) were considered to be associated
with a lower number of relapses/recurrences/suicide
attempts.
To identify factors associated with healthcare
resource use, random-intercept mixed linear regression
models were used, adjusted for participant level covariates (country, type of centre, demographics, medical
history, disease characteristics and characteristics of
index episode), to provide estimates of the adjusted
average difference in the incidence of visits per year.
As with the multivariate analyses for clinical
outcomes, the type of model was pre-specified, and
characteristics were included in the final multivariate
model based on clinical relevance and/or impact on
the univariate model. Clinical factors with a p value
<0.05 were considered to be associated with healthcare
resource use.
The characteristics considered for all multivariate
analyses included: country; site characteristics (type
of centre); patient demographics (sex, age, race, years
of education, professional status, degree of cohabitation, alcohol dependence, drug dependence); medical
history (any mental/psychiatric comorbidity, any
other medical condition, any family history of mental/psychiatric condition); disease characteristics
(type of BD, time from diagnosis, polarity of episode
at diagnosis, age at diagnosis, longest period of euthymia since diagnosis, lifetime presence of psychotic
symptoms and/or seasonal pattern and/or rapid
cycling, previous hospitalizations, suicidal behaviour);
study index episode characteristics (polarity of
index episode, duration of index episode, presence of
psychotic symptoms at index episode, treatments
prescribed).
1722 E. Vieta et al.
Fig. 1. Patient disposition. eCRF, Electronic case report
form.
Ethics
The study was conducted in accordance with ethical
principles consistent with the Declaration of Helsinki
2008 revised guidelines and the applicable legislation
on non-interventional studies. The study and the
informed consent form were reviewed and approved
by the leading Ethics Committee in each participating
country and all patients gave their informed consent.
Results
Study sample and baseline characteristics
In total, 2965 patients were enrolled in the WAVE-bd
study. Of these, 69 were excluded for unsigned or
lack of data in the electronic case report form, resulting
in 2896 patients being included in the final analysis
(Fig. 1). Patient demographics, co-morbidities and
bipolar disease history are shown in Table 1.
Demographics were broadly similar between
countries. Mean (S.D.) age of study participants was
46.7 (13.3) yr, more patients were female (62.0%), and
the majority were Caucasian [91.2% overall; >79.3%
in all countries except for Venezuela (36.9%)]. In all
countries, most patients lived accompanied, with the
percentage of patients living alone ranging from 6.2%
in Venezuela to 36.9% in France. A total of 19.9% of
patients suffered from at least one co-morbid psychiatric disorder, ranging from 1.8% in Brazil to 38.3% in
France. Overall, 25.8% of patients had a family history
of BD, ranging from 6.0% in Romania to 34.8% in
Belgium. The mean (S.D.) duration of prospective
follow-up was 416.6 (173.9) d overall. Turkey and
Brazil had the lowest mean prospective follow-up
[298.3 (99.4) and 298.9 (170.2) d, respectively], and
Germany the highest [502.1 (153.1) d; Table 1].
The polarity of study index episodes in each country
is shown in Fig. 2. The majority of study index episodes were depressive (53.4%), followed by mania
(22.0%) and hypomania (16.5%). Depression was the
most common type of study index episode for all
countries except Turkey, where it was mania (47.4%).
Overall, depressive index episodes tended to have a
longer duration than manic, hypomanic and mixed
index episodes [mean (S.D.) duration: 104 (101) d compared with 70 (81), 67 (67) and 79 (83) d, respectively].
However, duration varied between countries,
especially for index episodes of mixed polarity,
which had a much longer duration in Latin
American countries than in European countries
[mean (S.D.) duration was 181 (113) d in Brazil and
185 (136) d in Venezuela vs. a mean duration in
Europe ranging from 37 (30) d in Romania to 123
(143) d in Austria].
Clinical outcomes
Relapses
Relapses were reported by 18.2% of patients during the
study period (n = 526; Table 2). The proportion of
patients with reported relapse ranged from 6.2% in
Turkey to 34.4% in Austria. The IR of reported relapses
during the study was 1.562 per person-year (95% CI
1.465–1.664), ranging from 0.464 (95% CI 0.311–0.666)
in Turkey to 2.645 (95% CI 2.318–3.006) in Belgium.
This relatively high IR demonstrates that patients
reporting a relapse were likely to experience more
than one relapse over the course of the study. When
analysed by polarity, depressive relapses were the
most frequent in terms of the number of patients
(331 patients, 11.4%) and the IR [0.798 per person-year
(95% CI 0.729–0.872)]. Hypomanic relapses were the
second most frequent occurring in 5.9% of patients
[171 patients, IR 0.331 per person-year (95% CI
0.287–0.380)], followed by manic relapses which
occurred in 3.4% of patients (97 patients, IR 0.196 per
Table 1. Patient demographics, co-morbidities, and disease characteristics by country
n (%)
Demographics
Male, n (%)
Age, mean (S.D.)
Aged <65 yr, n (%)
Caucasian, n (%)
Years of education,
mean (S.D.)
Employed, n (%)
Living alone, n (%)
Not alcohol/drug
abusers, n (%)
Duration of prospective
follow-up, mean (S.D.)
Disease characteristics
Type BD I, n (%)
Rapid cycling, n (%)
Seasonal pattern, n (%)
Family history of BD, n (%)
Age (yr) at first symptoms,
mean (S.D.)
Age (yr) at diagnosis,
mean (S.D.)
Patients with previous
hospitalizations,†* n (%)
Patients with previous
suicide attempts,* n (%)
BD, Bipolar disorder.
† BD-related.
* From diagnosis to index episode.
Belgium
Brazil
France
Germany
Portugal
Romania
Turkey
Ukraine
Venezuela
Total
125 (4.3)
408 (14.1)
164 (5.7)
480 (16.6)
209 (7.2)
512 (17.7)
183 (6.3)
369 (12.7)
221 (7.6)
225 (7.8)
2896 (100)
35 (28.0)
51.8 (14.5)
97 (77.6)
123 (98.4)
12.6 (3.9)
178 (43.6)
50.0 (12.7)
358 (87.8)
406 (99.5)
13.2 (4.1)
58 (35.4)
45.0 (12.9)
155 (94.51)
130 (79.27)
10.1 (3.6)
166 (34.6)
46.8 (12.5)
448 (93.3)
411 (85.6)
11.1 (4.6)
85 (40.7)
50.0 (13.2)
179 (85.7)
209 (100)
9.7 (5.2)
181 (35.4)
48.5 (13.3)
448 (87.5)
508 (99.2)
11.5 (5.2)
76 (41.5)
49.0 (12.1)
167 (91.3)
183 (100)
12.9 (3.1)
171 (46.3)
38.3 (12.2)
362 (98.1)
367 (99.5)
9.9 (4.2)
90 (40.7)
43.1 (12.0)
214 (96.83)
221 (100)
13.8 (2.5)
60 (26.7)
46.4 (13.1)
207 (92.0)
83 (36.9)
11.8 (4.3)
1100 (38.0)
46.7 (13.3)
2635 (91.0)
2641 (91.2)
11.6 (4.5)
45 (36.0)
46 (36.8)
112 (89.6)
130 (31.9)
118 (28.9)
340 (83.3)
43 (26.2)
14 (8.5)
151 (92.1)
209 (43.5)
177 (36.9)
357 (74.4)
69 (33.0)
65 (31.1)
187 (89.5)
220 (43.0)
69 (13.5)
463 (90.4)
40 (21.9)
25 (13.7)
159 (86.9)
132 (35.8)
41 (11.1)
361 (97.8)
87 (39.4)
35 (15.8)
195 (88.2)
88 (39.1)
14 (6.2)
209 (92.9)
1063 (36.7)
604 (20.9)
2534 (87.5)
469.8
(170.2)
420.4
(200.6)
298.9
(170.2)
411.5
(181.8)
502.1
(153.1)
449.1
(180.3)
427.1
(116.8)
298.3
(99.4)
430.4
(121.0)
494.6
(150.3)
416.6
(173.9)
30 (24.0)
6 (4.8)
10 (8.0)
19 (15.2)
15 (12.0)
2 (1.6)
16 (12.8)
59 (14.5)
42 (10.3)
55 (13.5)
34 (8.3)
58 (14.2)
24 (5.9)
105 (25.74)
17 (10.4)
9 (5.5)
4 (2.4)
15 (9.2)
5 (3.05)
0 (0.0)
3 (1.8)
53 (11.0)
32 (6.7)
53 (11.0)
48 (10.0)
60 (12.5)
27 (5.6)
184 (38.3)
48 (23.0)
18 (8.61)
22 (10.5)
36 (17.2)
52 (24.9)
9 (4.3)
55 (26.3)
78 (15.2)
42 (8.2)
82 (16.0)
34 (6.6)
60 (11.7)
18 (3.5)
65 (12.7)
43 (23.5)
13 (7.1)
36 (19.7)
13 (7.1)
31 (16.9)
6 (3.3)
7 (3.8)
30 (8.1)
20 (5.4)
30 (8.1)
34 (9.2)
18 (4.9)
3 (0.8)
53 (14.4)
32 (14.5)
4 (1.8)
3 (1.4)
8 (3.6)
7 (3.2)
2 (0.9)
50 (22.6)
33 (14.7)
10 (4.4)
29 (12.9)
24 (10.7)
42 (18.7)
22 (9.8)
39 (17.3)
423
196
324
265
348
113
577
86 (68.8)
20 (16.0)
31 (24.8)
19 (15.2)
32.0 (14.0)
260 (63.7)
94 (23.0)
91 (22.3)
142 (53.8)
32.4 (13.8)
136 (82.9)
16 (9.8)
4 (2.4)
37 (22.6)
29.0 (12.2)
285 (59.4)
72 (15.0)
118 (24.6)
154 (32.1)
31.0 (11.6)
132 (63.2)
43 (20.6)
31 (14.8)
37 (17.7)
31.4 (12.7)
331 (64.7)
86 (16.8)
180 (35.2)
164 (32.0)
32.3 (12.6)
165 (90.2)
12 (6.6)
20 (10.9)
11 (6.0)
38.7 (12.9)
301 (81.6)
106 (28.7)
135 (36.6)
100 (27.1)
26.3 (32.3)
136 (61.5)
30 (13.6)
65 (29.4)
15 (6.8)
31.7 (11.6)
157 (69.8)
28 (12.4)
25 (11.1)
69 (30.7)
29.4 (11.4)
1989 (68.7)
507 (17.51)
700 (24.2)
748 (25.8)
31.1 (12.4)
37.9 (14.8)
36.5 (13.9)
33.3 (12.6)
35.9 (11.8)
35.9 (12.3)
35.8 (12.6)
40.6 (13.2)
27.4 (10.0)
34.9 (11.5)
34.5 (12.6)
34.9 (12.8)
93 (74.4)
252 (61.76)
86 (52.4)
336 (70.0)
157 (75.1)
309 (60.4)
168 (91.8)
221 (59.9)
176 (79.6)
146 (64.9)
1944 (67.1)
28 (22.4)
98 (24.0)
48 (28.3)
136 (28.3)
51 (24.4)
78 (15.2)
31 (16.9)
61(16.5)
19 (8.6)
45 (20.0)
595 (20.6)
(14.6)
(6.8)
(11.2)
(9.2)
(12.0)
(3.9)
(19.9)
Clinical management and burden of BD:WAVE-bd 1723
Co-morbidities
High blood pressure, n (%)
Diabetes, n (%)
Dyslipidaemia, n (%)
Thyroid disease, n (%)
Obesity, n (%)
Metabolic syndrome, n (%)
Any co-morbid psychiatric
disorder, n (%)
Austria
1724 E. Vieta et al.
100
Mania
Hypomania
Patients (%)
80
Depression
Mixed
60
NOS
Unknown
40
Missing
20
0
Aus Bel Bra Fra Ger Por Rom Tur Ukr Ven Total
Fig. 2. Polarity of study index episode by country. NOS,
Not otherwise specified; Aus, Australia; Bel, Belgium; Bra,
Brazil; Fra, France; Ger, Germany; Por, Portugal; Rom,
Romania; Tur, Turkey; Ukr, Ukraine, Ven, Venezuela.
person-year (95% CI: 0.163–0.235)] and mixed relapses
which occurred in 3.0% of patients [86 patients, IR
0.182 per person-year (95% CI 0.150–0.219)].
Depressive relapse was the most common type of
reported relapse in all countries except Romania,
where the most common type of reported relapse
was mixed relapse (13.1%).
In multivariate Poisson regression analysis (Table 3),
seven variables were identified as independent risk
factors for a higher number of reported relapses
(mean IRR >1.05, p<0.05). These were: recruitment
from a primary care centre; at least one suicide attempt
from diagnosis to study index episode; the presence of
rapid cycling; aged 565 yr; living alone; having a
family history of mental illness; being prescribed antidepressants during the study index episode. Variables
associated with a lower number of reported relapses
(mean IRR <0.95, p<0.05) were recruitment from a mental health centre and an extended period of euthymia
from diagnosis to study index episode.
Recurrences
Recurrences were reported by 40.5% of patients
during the study period (n = 1173), ranging from
20.1% in Turkey to 63.2% in Austria (Table 2). The IR
of reported recurrences was 0.691 per person-year
(95% CI 0.657–0.726), ranging from 0.347 (95% CI
0.275–0.433) in Turkey to 1.125 (95% CI 0.921–1.360).
Depressive recurrences were the most common
[23.1% of patients (n = 670); IR 0.352 per person-year
(95% CI 0.328–0.377)], followed by hypomanic [10.1%
of patients (n = 293); IR 0.145 per person-year (95% CI
0.130–0.161)], manic [6.5% of patients (n = 189); IR
0.090 per person-year (95% CI 0.078; 0.104)] and
mixed recurrences [4.8% of patients (n = 139); IR 0.078
per person-year (95% CI 0.067–0.090)]. Depressive
recurrence was the most common type of reported
recurrence in all countries except for Romania, where
the most common type of reported recurrence was
mixed recurrence (25.7%).
Multivariate Poisson regression analysis (Table 3)
identified four risk factors associated with a higher
number of recurrences (mean IRR >1.05, p<0.05).
These were: current alcohol or drug abuse and/or
dependence; a family history of mental illness; experiencing a rapid cycling disease pattern at any time
point; being prescribed anxiolytics, sedatives or hypnotics during the study index episode. No variables
were found to be associated with a lower number of
reported recurrences (mean IRR <0.95).
Suicide attempts
From the onset of the study index episode, 99 patients
attempted suicide (3.4% of the study population), and
one suicide was reported during the 12–27-month
study period (Table 2). The proportion of patients
attempting suicide was lowest in Turkey (0.8%) and
Ukraine (1.8%), and was highest in Belgium (5.6%)
and France (5.2%). The reported IR of suicide attempts
was 0.030 per person-year (95% CI 0.025–0.036), and
ranged from 0.008 (95% CI 0.002–0.025) in Turkey to
0.057 (95% CI 0.040–0.080) in Belgium.
In multivariate Poisson regression analysis, two
variables were identified as independent risk factors
for a higher number of suicide attempts (mean IRR
>1.05). These were any suicide attempt from diagnosis
to study index episode, and being prescribed antidepressants during the study index episode. No variables were found to be associated with a lower
number of suicide attempts during this study (mean
IRR <0.95).
Clinical management
Medication
Medication polytherapy was common throughout
all phases of the disease; patients were prescribed a
mean (S.D.) number of 2.84 (1.49) treatments in
mania, 2.61 (1.32) treatments in hypomania, 3.11
(1.53) treatments in depression, 3.17 (1.51) treatments
in mixed episodes and 2.87 (1.45) treatments during
euthymia.
The medications prescribed during each disease
phase, analysed by patient, are shown in Fig. 3.
Lithium was prescribed in ∼30% of patients irrespective of disease phase (mania, 33.2%; hypomania,
30.5%; depression, 26.5%; mixed 27.2%; euthymia,
29.0%). Anticonvulsant use was also reasonably
consistent across disease phases (mania, 63.1%;
hypomania, 60.3%; depression, 59.4%, mixed 66.0%;
99 (3.4)
6 (2.7)
4 (1.8)
3 (0.8)
5 (2.7)
14 (2.7)
8 (3.8)
25 (5.2)
n, Number of patients.
23 (5.6)
3 (2.4)
Suicide attempts
All
8 (4.9)
1173 (40.5)
189 (6.5)
293 (10.1)
670 (23.1)
139 (4.8)
100 (44.4)
31 (13.8)
22 (9.8)
48 (21.3)
11 (4.9)
90 (40.7)
15 (6.8)
33 (14.9)
39 (17.7)
9 (4.1)
74 (20.1)
23 (6.2)
16 (4.3)
30 (8.1)
5 (1.4)
93 (50.8)
18 (9.8)
5 (2.7)
35 (19.1)
47 (25.7)
224 (43.8)
21 (4.1)
62 (12.1)
136 (26.6)
21 (4.1)
107 (51.2)
13 (6.2)
21 (10.1)
83 (39.7)
6 (2.9)
176 (36.7)
14 (2.9)
64 (13.3)
114 (23.8)
11 (2.3)
47 (28.7)
12 (7.3)
14 (8.5)
18 (11.0)
5 (3.1)
79 (63.2)
14 (11.2)
13 (10.4)
49 (39.2)
8 (6.4)
Recurrences
All
Manic
Hypomanic
Depressive
Mixed
183 (44.9)
28 (6.9)
43 (10.5)
118 (28.9)
16 (3.9)
526 (18.2)
97 (3.4)
171 (5.9)
331 (11.4)
86 (3.0)
35 (15.6)
12 (5.3)
13 (5.8)
17 (7.6)
2 (0.9)
36 (16.3)
6 (2.7)
10 (4.5)
18 (8.1)
13 (5.9)
23 (6.2)
3 (0.8)
6 (1.6)
12 (3.3)
0 (0.0)
35 (19.1)
11 (6.0)
5 (2.7)
5 (2.7)
24 (13.1)
(17.2)
(2.9)
(5.7)
(10.7)
(2.5)
88
15
29
55
13
58 (27.8)
10 (4.8)
18 (8.6)
44 (21.1)
4 (1.9)
77 (16.0)
3 (0.6)
25 (5.2)
55 (11.5)
6 (1.3)
102 (25.0)
25 (6.1)
42 (10.3)
75 (18.4)
11 (2.7)
43 (34.4)
7 (5.6)
15 (12.0)
32 (25.6)
8 (6.4)
29 (17.7)
5 (3.1)
8 (4.88)
18 (11.0)
5 (3.1)
2896 (100)
225 (7.8)
221 (7.6)
369 (12.7)
183 (6.3)
512 (17.7)
209 (7.2)
480 (16.6)
164 (5.7)
408 (14.1)
125 (4.3)
n (%)
Relapses
All
Manic
Hypomanic
Depressive
Mixed
Belgium
Austria
Table 2. Clinical outcomes by country
Brazil
France
Germany
Portugal
Romania
Turkey
Ukraine
Venezuela
Total
Clinical management and burden of BD:WAVE-bd 1725
euthymia, 62.8%). However, there were variations in
the type of anticonvulsant used depending on disease
phase. Valproic acid was the most commonly used
anticonvulsant in all disease phases, being prescribed
more frequently in manic (45.3% of patients) and
mixed episodes (43.3% of patients) and used less frequently in depression (29.3% of patients). As expected,
antidepressant use was highest in depression (71.7% of
patients) although a moderately high proportion of
euthymic patients were also receiving antidepressants
(49.7% of patients). In addition, 16.5% of patients
with mania and 32.0% of patients with hypomania
also received antidepressants. The most commonly
prescribed antidepressants were selective serotonin
reuptake inhibitors, followed by serotonin–norepinephrine reuptake inhibitors, across all disease phases
(Fig. 3). Antipsychotics were the most commonly used
drug class in all episode types except depressive episodes, where antidepressants were more commonly
prescribed. The percentage of patients that received
antipsychotics was 85.2% in mania, 73.3% in hypomania, 63.2% in depression, 74.0% in mixed episodes and
69.7% in euthymia. The use of atypical antipsychotics
was far higher than that of typical antipsychotics in
these patients (Fig. 3). Anxiolytics, sedatives and hypnotics were prescribed more frequently in mixed episodes (39.1% of patients) and depressive episodes
(33.5% of patients) than in mania (23.1% of patients),
hypomania (26.7% of patients) and euthymia (28.7%
of patients).
During the study, 11.0% of patients experiencing a
manic episode received no medication. Similarly, the
percentage of patients that received no medication in
hypomanic, depressive and mixed episodes was 10.4,
7.8 and 6.3%, respectively. Unexpectedly, the phase
of the disease where the most patients were prescribed
pharmacological treatment was euthymia, where only
6.1% did not receive medication.
The percentage of patients who received no medication was comparable between countries for all episode types and was consistently lowest in Turkey.
Treatments received were generally similar between
countries, overall and according to disease phase
(Supplementary Table S2). One notable exception
was the proportion of patients treated with lithium
during a manic episode which varied considerably
between countries, ranging from 3.4% in Romania to
58.3% in Brazil. Atypical antipsychotics were the
most common specific treatment in patients during
euthymia in all countries except Brazil, where lithium
was more commonly used.
The longest duration of pharmacological treatment
was observed with valproic acid, which patients
1726 E. Vieta et al.
Table 3. Factors associated with number of reported relapses (a) and recurrences (b)
(a)
Factor
Relapses
IRR (95% CI)
p value
Aged 565 yr
Female
Current alcohol/drug abuser
Living alone
Type BD-I
Familial mental illness
Rapid cycling
Anxiety disorder
Thyroid disease
Longer period of euthymia since diagnosis
Suicide attempt between diagnosis and index episode
Longer time from diagnosis to index episode
Higher no. hospitalizations due to BD since diagnosis
Manic/hypomanic index episode
Depressive index episode
Mixed index episode
Enrolled from hospital
Enrolled from private practice
Enrolled from mental health centre
Enrolled from primary care
Older age at first BD symptoms
Longer duration between symptoms and diagnosis
Received antidepressants during index episode
1.514 (1.046–2.190)
0.916 (0.753–1.114)
1.219 (0.960–1.548)
1.312 (1.068–09.36)
1.176 (0.936–1.476)
1.853 (1.496–2.295)
1.862 (1.541–2.251)
0.798 (0.618–1.031)
1.000 (0.739–1.353)
0.996 (0.992–1.000)
1.972 (1.628–2.389)
0.994 (0.984–1.006)
0.983 (0.960–1.006)
3.503 (0.484–25.344)
3.224 (0.447–23.235)
5.243 (0.714–38.522)
1.065 (0.844–1.343)
1.204 (0.975–1.487)
0.273 (0.163–0.457)
2.862 (2.051–3.992)
0.997 (0.987–1.007)
1.011 (0.998–1.024)
1.385 (1.122–1.711)
0.028
0.381
0.104
0.010
0.164
<0.001
<0.001
0.085
0.999
0.027
<0.001
0.241
0.137
0.214
0.245
0.103
0.596
0.084
<0.001
<0.001
0.514
0.098
0.002
Factor
Recurrences
IRR (95% CI)
p value
Aged 565 yr
Female
Current alcohol/drug abuser
Familial mental illness
Seasonal pattern
Rapid cycling
Anxiety disorder
Thyroid disease
High BP, diabetes or obesity
Longer period of euthymia since diagnosis
Suicide attempt between diagnosis and index episode
Longer time from diagnosis to index episode
Higher no. hospitalizations due to BD since diagnosis
Enrolled from hospital
Enrolled from private practice
Enrolled from mental health centre
Enrolled from primary care
Older age at first BD symptoms
Longer duration between symptoms and diagnosis
Received anticonvulsants during index episode
1.114 (0.813–1.528)
1.099 (0.933–1.294)
1.623 (1.321–1.995)
1.288 (1.099–1.508)
1.130 (0.953–1.340)
1.370 (1.143–1.642)
0.873 (0.699–1.092)
1.070 (0.844–1.355)
1.008 (0.851–1.195)
0.992 (0.989–0.995)
1.098 (0.918–1.315)
1.003 (0.993–1.013)
1.024 (1.007–1.042)
1.081 (0.859–1.360)
1.134 (0.914–1.408)
0.600 (0.340–1.060)
1.359 (0.999–1.848)
0.993 (0.986–1.001)
1.006 (0.994–1.018)
0.957 (0.817–1.122)
0.501
0.257
<0.001
0.002
0.159
0.001
0.234
0.576
0.925
<0.001
0.306
0.614
0.006
0.509
0.253
0.078
0.051
0.103
0.304
0.589
(b)
Clinical management and burden of BD:WAVE-bd 1727
Table 3. (Cont.)
(b)
Factor
Recurrences
IRR (95% CI)
p value
Received antipsychotics during index episode
Received anxiolytics, sedative/hypnotics during index episode
1.087 (0.920–1.286)
1.213 (1.026–1.435)
0.326
0.024
BD, Bipolar disorder; BP, blood pressure; IRR, incidence rate ratio; CI, confidence interval.
In total, 1410 relapses and 1332 recurrences were included in the analyses. The IRR is the incidence rate of the stated factor over
the ‘opposite’ factor (defined as all other non-missing data collected). Factors associated with a higher or lower incidence of
relapse/recurrence are shown in bold. IRRs with 95% CI were calculated by Poisson regression multivariable analysis adjusted
for type of centre, demographics, medical history, disease characteristics and characteristics of index episode. Only clinical factors
included in the final model are shown. Countries were included in the model but are not shown. Clinical factors with a mean IRR
>1.05 and p value <0.05 were considered factors associated with a higher number of relapses/recurrences. Clinical factors with a
mean IRR <0.95 and p value <0.05 were considered factors associated with a lower number of relapses/recurrences.
received for a mean (S.D.) length of 157.7 (262.0) d
(Supplementary Table S3). This was followed by
lithium [140.7 (260.2) d], quetiapine extended release
[79.3 (196.6) d], lamotrigine [76.2 (198.1) d] and olanzapine [62.6 (171.9) d].
Healthcare resource use
The frequency of visits to different healthcare centres
was measured over the course of the study to assess
the burden of BD on healthcare resources. From the
onset of the index episode to the end of the study,
the IR of visits to all healthcare centres was 11.17 per
person-year (95% CI 11.06–11.27). Patient use of
healthcare resources was similar between countries,
and ranged from IR 7.62 (95% CI 7.43–7.81) in
Portugal to 19.12 (95% CI 18.51–19.74) in Austria.
The most frequently accessed healthcare resource was
the psychiatrist [IR 7.51 per person-year (95% CI
7.43–7.60)] with programmed visits to the psychiatrist
more common than spontaneous visits [IR 6.796 per
person-year (95% CI 6.72–6.88) vs. 0.715 per personyear (95% CI 0.690–0.742)]. Programmed visits to psychiatrists were the biggest single healthcare resource
used by patients in all countries, with IRs ranging
from 5.04 (95% CI 4.80–5.30) in Ukraine to 9.42 (95%
CI 9.04–9.82) in Romania. Other less frequently
accessed resources were the psychologist [IR 1.366
per person-year (95% CI 1.33–1.40)], primary care [IR
0.772 per person-year (95% CI 0.75–0.80)] and group
therapy [0.521 per person-year (95% CI 0.50–0.54)].
The IR of hospitalizations was 0.247 per person-year
(95% CI 0.23–0.26) and visits to the emergency room
had IR 0.138 per person-year (95% CI 0.13–0.15).
In general, patients in Romania, Austria and
Germany used healthcare resources most frequently,
and patients in Brazil, Venezuela, Turkey, Portugal
and Ukraine used healthcare resources less frequently.
In multivariate mixed linear regression analysis,
variables found to be associated with a higher total
healthcare resource use were rapid cycling, thyroid disease, treatment with antipsychotics during the study
index episode and a higher number of hospitalizations
from diagnosis to the study index episode. The only
variable found to be associated with a lower incidence
of total healthcare resource use was recruitment from a
mental health centre.
Discussion
This is the primary report from the large WAVE-bd
study, which was designed to describe clinical management and clinical outcomes related to BD in real-life
settings from different countries. The results indicate
that certain disease characteristics tend to be the
same across geographical and cultural backgrounds,
while others and particularly certain outcomes such
as the intensity of care devoted to each illness phase
(mania, depression) may change quite substantially
depending on the healthcare system of each country.
The study shows that relapses are very common
(≤18% during the 12–27-month study, mostly depressive) and that this is a highly recurrent illness, with
>40% of the patients experiencing a recurrence during
the study, despite the fact that almost all patients (94%)
were on maintenance treatment. The high morbidity of
BD is well documented (Judd et al., 2003; Perlis et al.,
2006; de Dios et al., 2012); analyses carried out in this
1728 E. Vieta et al.
Anticonvulsants Anxiolytics Antipsychotics
NRIs
MAOIs
SSRIs
SNRIs
Tricyclic
0
Tetracyclic
10
Antidepressants
Antidepressants
(d)
Antidepressants
20
Anticonvulsants Anxiolytics Antipsychotics
NRIs
MAOIs
SSRIs
SNRIs
0
Tricyclic
10
Tetracyclic
NRIs
MAOIs
SSRIs
SNRIs
Tricyclic
Anticonvulsants Anxiolytics Antipsychotics
Tetracyclic
Typical
Atypical
Other
Benzodiazepines
Valproic acid
Lamotrigine
Carbamazepine
0
Lithium
10
30
Typical
20
40
Atypical
30
50
Other
40
60
Benzodiazepines
50
70
Valproic acid
60
80
Lamotrigine
70
Carbamazepine
80
Lithium
Patients receiving treatment (%)
(c)
Patients receiving treatment (%)
20
Typical
NRIs
MAOIs
SSRIs
SNRIs
Tricyclic
Anticonvulsants Anxiolytics Antipsychotics
Tetracyclic
Typical
Atypical
Other
Benzodiazepines
Lamotrigine
Valproic acid
0
Carbamazepine
10
30
Atypical
20
40
Other
30
50
Benzodiazepines
40
60
Lamotrigine
50
70
Valproic acid
60
80
Carbamazepine
70
Lithium
Patients receiving treatment (%)
(b)
80
Lithium
Patients receiving treatment (%)
(a)
Antidepressants
80
70
60
50
40
30
20
Anticonvulsants Anxiolytics Antipsychotics
NRIs
MAOIs
SSRIs
SNRIs
Tricyclic
Tetracyclic
Typical
Atypical
Other
Benzodiazepines
Valproic acid
Lamotrigine
0
Carbamazepine
10
Lithium
Patients receiving treatment (%)
(e)
Antidepressants
Fig. 3. Pharmacological treatments prescribed in each disease phase during the study. Medications prescribed in mania
(a), hypomania (b), depression (c), mixed episodes (d), and euthymia (e) are presented. * Percentages for treatment are
calculated with regard to patients with at least one manic/hypomanic/depressive/mixed episode or euthymia period with any
treatment. MAOI, Monoamine oxidase inhibitor; NRI, noradrenaline reuptake inhibitor; SNRI, serotonin–norepinephrine
reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
study indicate that factors leading to relapses and
recurrences include alcohol/drug abuse, family history
of mental illness, rapid cycling, short duration of
euthymia, previous suicide attempts and more hospitalizations. This is consistent with previous literature;
several small studies and a few large ones have
observed that patients with substance use
co-morbidity are more likely to recur and to be poorly
adherent to medication (Colom et al., 2000; Mantere
et al., 2010; Ostacher et al., 2010). Moreover, family
Clinical management and burden of BD:WAVE-bd 1729
history has been reported to be relevant to outcome
(Romero et al., 2007; Baldessarini et al., 2012), and
rapid cycling is a well-known factor leading to poor
short- as well as long-term outcome (Lee et al., 2010;
Undurraga et al., 2012). Short periods of euthymia
may be a proxy of subclinical symptoms, which have
been consistently reported to predict recurrences
(Perlis et al., 2006). Our study highlights an association
between use of antidepressants (during the index episode) and an increased risk of both relapse and suicide
attempts. This could be interpreted as representing
patients with depressive symptoms; these patients
being more prone to relapse, recurrence or suicide
attempt. However, as a relatively high number of
patients in manic and hypomanic phases of the disease
also received antidepressants, this association may also
reflect that antidepressant use is a risk factor for
relapse, recurrence or suicide attempt in this group of
patients. An excessive use of antidepressant has also
been reported in other surveys (Grande et al., 2012).
Suicide attempts have also been reported to be more
frequent in patients who are more prone to relapse
(Bellivier et al., 2011) and hospitalizations obviously
correlate with recurrences. The Predictors of
Recurrence in Bipolar Disorder in Spain study (de
Dios et al., 2012) identified other factors, such as living
in rural or small urban areas, and being severely disabled, as predictive factors for relapse and recurrence,
which were not confirmed in this study. Taken
together, the predictors identified in this study are
clinical markers of longitudinal severity, which
confirm the findings of previous studies.
The findings concerning medication are somewhat
less obvious: the mean number of drugs per patient
was about three, confirming that polytherapy is
the rule rather than the exception, regardless of guideline recommendations (Nivoli et al., 2011, 2012).
Prescription patterns indicate that clinicians are
aware that anticonvulsants are not a class in BD
(Fountoulakis et al., 2011; Rosa et al., 2011), given the
sharp differences in patients’ profile among valproate,
carbamazepine and lamotrigine. Another relevant
finding is the low rate of lithium use in all phases of
the disease, although lithium has been considered by
many ‘the cornerstone’ of the treatment of manicdepressive illness (Nivoli et al., 2010). This may be
the result of varying cultural differences in prescription
and marketing across countries; in some countries,
lithium may be perceived as ‘unsafe’ because of the
risk of intoxication, which might have been emphasized by competitors in certain places. Lithium is an
orphan drug and is not promoted at all nowadays.
The use of antidepressants was very high (≤50% in
maintenance) despite the very limited evidence base
supporting that practice (Fountoulakis et al., 2011;
Pacchiarotti et al., 2011). Even 16% of manic patients
received antidepressants, as reported independently
by Rosa et al. (2011) in the European Mania in
Bipolar Longitudinal Evaluation of Medication study
(Rosa et al., 2010) and despite concerns about drugs
of this class exacerbating manic symptoms (Perlis
et al., 2010; Valentí et al., 2012). Hence, prescribers
seemed to have little awareness of the risk of switch
into mania or mixed episodes (Valentí et al., 2011,
2012; Undurraga et al., 2012) or, if they were, they
seemed to prefer to take the risk rather than avoiding
the use of antidepressants. However, the study
shows lower antidepressant prescription trends than
a US study (Baldessarini et al., 2008) and wider
use of antipsychotics across all phases, including
depression. The use of antipsychotics beyond the traditional mania indication may reflect the increasing
evidence base for their use in maintenance (Vieta
et al., 2011) and, in some cases, in depression (Cruz
et al., 2010). Another striking finding was the greater
use of anxiolytics in patients with mixed episodes,
suggesting a clear link between anxiety and mixed features as reported by Koukopoulos (1995), Young et al.
(1993) and González-Pinto et al. (2012).
The findings of this study also indicate that BD is a
source of clinical burden, which is linked to a high
healthcare resource use; the incidence of visits to the
psychiatrist was 7.5 per person-year and the incidence
of total visits to psychiatrist, psychologist, primary
care, group therapy and emergency room was 11.2
per person-year.
Despite the large sample size and all the efforts to
include a representative sample of patients from
every country, this study has limitations. In terms of
generalizability, the study did not involve countries
from all over the world but selected countries from
Europe and South America and, as pointed out previously, important differences between countries
exist. Therefore, the results can be considered representative of everyday clinical practice in the selected
countries but not beyond those. The study was naturalistic and the diagnosis was made according to
DSM-IV criteria, but no standardized interview was
used. However, the study population consisted of BD
patients with a disease duration of several years,
suggesting that diagnostic confidence was high. In
addition, a number of scales and systematic assessments were made concerning course and outcome
(life chart, Functional Assessment Short Test Scale,
Clinical Global Impressions and several other
scales as reported previously; Vieta et al., 2011).
1730 E. Vieta et al.
Baseline information on factors such as weight and
smoking status is also lacking. Another major limitation of the study is that suicides were not recorded,
so only attempted suicides could be detected. The
report of only one suicide was by chance and is
lower than previously published data (Tondo et al.,
2007; Dennehy et al., 2011). It is likely that more
suicides occurred in the lost-to-follow-up group.
In summary, the WAVE-bd study provides insights
into the treatment patterns for BD across different
countries in Europe and South America, and on factors
related to relapse and recurrence. The study highlights
the increasing use of antipsychotics in BD and the variation in lithium prescription between countries.
Combinations of several drugs are commonly used
beyond acute episodes and this may be closely related
to the high use of healthcare resources found to be
associated to this condition.
Otsuka and the European Space Agency. D. Souery
has been a member of advisory boards for
AstraZeneca, Lundbeck, Bristol-Myers Squibb, and Eli
Lilly and has received an unrestricted grant from
Lundbeck. He is involved in clinical trials supported
by Eli Lilly, Novartis, and AstraZeneca. J.M. Langosch
has received lecture fees from AstraZeneca, Pfizer,
Wyeth, Janssen-Cilag, Eisai and reimbursements for
being an advisory board member for AstraZeneca
and Bristol-Myers Squibb. E. Medina is a previous
employee of AstraZeneca. M. Moreno-Manzanaro is
an employee of AstraZeneca. M.A. Gonzalez is an
employee of the research organization Quintiles; performed statistical analyses; had full access to the raw
data set and received funding from AstraZeneca for conducting the analyses.
Supplementary material
Acknowledgements
This study was funded by AstraZeneca. Susie Parker of
Fishawack Communications Ltd provided medical
writing support, funded by AstraZeneca. The authors
are grateful to the investigators involved in the study.
[Clinicaltrials.gov registration number NCT01062607,
Study of the Clinical Management of Bipolar Disease
(WAVE bd), http://clinicaltrials.gov/ct2/results?term=
NCT01062607]
Statement of Interest
E. Vieta has received grants and served as consultant,
advisor or CME speaker for Almirall, AstraZeneca,
Bristol-Myers Squibb, Eli Lilly, Forest Research
Institute,
Gedeon
Richter,
GlaxoSmithKline,
Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck,
Merck,
Novartis,
Organon,
Otsuka,
Pfizer,
Pierre-Fabre, Roche, Qualigen, sanofi-aventis, Servier,
Schering-Plough, Solvay, Takeda, Teva, the Spanish
Ministry of Science and Innovation (CIBERSAM),
the Seventh European Framework Programme
(ENBREC), the Stanley Medical Research Institute
and United Biosource Corporation and Wyeth. M. L.
Figueira has served as a consultant, advisor or speaker
for AstraZeneca, Bristol-Myers Squibb, Eli Lilly,
Janssen-Cilag,
sanofi-aventis,
Servier,
Pfizer,
Pierre-Fabre and Lundbeck. She has received grants
from The Foundation for Science and Technology
(Ministry of Science, Portugal). F. Bellivier has received
grants and served as consultant, advisor or speaker
for AstraZeneca, Bristol-Myers Squibb, Eli Lilly,
sanofi-aventis, Euthérapie, Janssen-Cilag, Lundbeck,
For supplementary material accompanying this paper,
visit http://dx.doi.org/10.1017/S1461145713000278
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