European Neuropsychopharmacology (]]]]) ], ]]]–]]]

www.elsevier.com/locate/euroneuro

Efficacy of quetiapine XR vs. placebo

as concomitant treatment to mood stabilizers
in the control of subthreshold symptoms
of bipolar disorder: Results from a pilot,
randomized controlled trial
Marina Garrigaa,1, Eva Soléa,1, Ana González-Pintob,
Gabriel Selva-Verac, Belén Arranzd, Benedikt L. Amanne,
Jerónimo Saiz-Ruizf, Josefina Pérez-Blancog, Eduard Vietaa,n

a
Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clinic Barcelona, IDIBAPS, CIBERSAM,
University of Barcelona, Barcelona, Catalonia, Spain
b
BioAraba Research Institute, OSI Araba, Department of Psychiatry, Araba University Hospital, CIBERSAM,
University of the Basque Country (EHU/UPV), Vitoria, Spain
c
Department of Psychiatry, University of Valencia. Hospital Clínico Valencia, INCLIVA, CIBERSAM, Valencia,
Spain
d
Department of Psychiatry, Parc Sanitari Sant Joan de Déu, CIBERSAM, Sant Boi de Llobregat, Barcelona,
Spain
e
Institut de Neuropsiquiatria i Addiccions, Hospital del Mar, Institut Hospital del Mar d'Investigacions
Mèdiques (IMIM), Research Unit Centro Fórum, CIBERSAM, Department of Psiquiatry,
Autonomous University Barcelona, Spain
f
Hospital Ramón y Cajal. University of Alcalá. CIBERSAM, IRYCIS. University of Alcalá, Alcalá de Henares,
Madrid, Spain
g
Department of Psychiatry, Hospital de Sant Pau, CIBERSAM, Barcelona, Spain

Received 6 April 2017; received in revised form 13 July 2017; accepted 20 August 2017

KEYWORDS Abstract
Bipolar disorder; Patients with bipolar disorder (BD) do not always achieve full remission between episodes.
Quetiapine; Subthreshold symptoms (depressive, manic or mixed) represent a major cause of relapse and
Subthreshold disability in these patients. Immediate release (IR) and extended release (XR) formulations of
symptoms quetiapine are both indicated for short and long-term treatment of BD. The aim of this study
was to evaluate the efficacy of quetiapine XR vs placebo in subthreshold symptomatology when

n
Correspondence to: Hospital Clínic, 170 Villarroel St., 08036 Barcelona, Catalonia, Spain. Fax: +34932275795.
E-mail address: evieta@clinic.ub.es (E. Vieta).
1
These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
0924-977X/& 2017 Elsevier B.V. and ECNP. All rights reserved.

Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
2 M. Garriga et al.

added to previous mood stabilizer treatment. A pilot phase IIIB, multicentre, prospective,
placebo controlled, randomized, double blinded study of 12 weeks follow-up was performed
(NCT01197846). Patients were randomized to quetiapine XR 300 mg or placebo once daily. The
primary outcome was the mean change between quetiapine XR and placebo from baseline to
study endpoint (week 6) in the Montgomery-Åsberg Depression Rating Scale (MADRS).
Quetiapine XR 300 mg (n= 16) significantly improved depressive subthreshold symptoms
compared with placebo (n =16) after 6 weeks (P =0.021). Early response (reduction of at least
the 20% of the MADRS total score) and remission rate (reduction in MADRS total score o8 and
YMRSo8) did not show differences between groups. Quetiapine XR did not show superiority vs
placebo when evaluating subthreshold manic symptoms, instead it was superior when
evaluating functioning (GAF score) in BD type I patients (P=0.005). The most common adverse
events were somnolence (9.1%), increased appetite, dry mouth and dizziness (6.8%). Quetiapine
XR 300 mg once daily was significantly more effective than placebo in depressive subthreshold
symptoms. Adverse events were consistent with the known side effects of quetiapine.
& 2017 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction assess efficacy in terms of (hypo)manic subthreshold symp-

Bipolar disorder (BD) is a psychiatric condition defined by
the presence of periodic episodes of mania/hypomania and
depression. The lifetime prevalence of BD I, BD II, and
subthreshold BD is approximately 2–4% of the general
population (Merikangas et al., 2007; Suttajit et al., 2014).
The course of the disease is recurrent and often virulent,
characterized by poor prognostic features such as rapid
cycling, treatment resistance, comorbidities and cognitive
and functional disability (Grande et al., 2016).
Ongoing depressive symptoms are, with cognitive defi-
cits, the strongest predictor of functional impairment in
persons with BD (Bonnin et al., 2014; Martinez-Aran and
Vieta, 2015; Samalin et al., 2017). Many patients do not
achieve full remission and subthreshold depressive symp-
toms, which are much more common than subthreshold
(hypo)manic symptoms, are a major cause of relapse and
disability (Judd et al., 2005; Yatham et al., 2004; Sanchez-
Moreno et al., 2009; Samalin et al., 2016; Vieta and Garriga
2016; Radua et al., 2017) and risk of suicide (Jiménez et al.,
2016). However, there are no pharmacological trials addres-
sing the treatment of bipolar patients with subthreshold
depressive symptoms, whereas this represents a vital unmet
need in the field of BD.
Quetiapine is an orally administered second generation
antipsychotic that has shown efficacy across all poles of the
disease and as maintenance treatment (Grande et al.,
2016). Both immediate release (IR) and extended release
(XR) formulations are indicated for the short and long-term
treatment of BD. So far, quetiapine has never been studied
in bipolar patients with subthreshold symptomatology.
1.1. Objectives
The primary objective of this study was to evaluate the
efficacy of quetiapine XR compared with placebo, in bipolar
patients with subthreshold symptoms when added to pre-
vious mood stabilizer treatment (lithium/valproate/lamo-
trigine). As secondary outcomes, investigators aimed to also
toms, functioning and safety profile.
2. Experimental procedures
2.1. Study design
This was a pilot phase IIIB, multicentre, prospective, placebo
controlled, randomized double blinded study of 12 weeks follow-
up, conducted in 10 Spanish centers between September 2010 and
September 2012 (Study D1443L00079; ClinicalTrials.gov identifier:
NCT01197846). It was a two phase trial with a first screening period
of two weeks and a second double-blind randomized period of 12
weeks, with a primary endpoint at week 6. Patients were randomly
assigned as outpatients to receive in a 1:1 ratio either quetiapine
XR or placebo once daily in the evening.
The study was performed in accordance with the ethical
principles of the Declaration of Helsinki and was consistent with
the International Conference on Harmonization (ICH)/Good Clinical
Practice (GCP). All patients provided written informed consent.
Patients and their parents or guardians could request withdrawal
from the study at any time. The study had the approval of all local
institutional review boards.
2.2. Patients
Inclusion criteria were male and female adult outpatients (18–65
years of age) with a documented Diagnostic and Statistical Manual
of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of
BD I or II. Eligible patients were also required to present a previous
treatment with no more than two concomitant mood stabilizers
(lithium, valproate or lamotrigine) at stable doses for at least
6 weeks prior to the trial, current subthreshold symptoms (defined
as YMRSr 14 and/or MADRSZ 8 and r14), and past history of at
least one manic, mixed, or depressed episode in the last 5 years.
Exclusion criteria were pregnancy or nursing, mental retarda-
tion, current active diagnosis of any axis I or II (DSM-IV-TR) different
from BD I or II, except of nicotine, caffeine abuse-dependence and
alcohol and/or substances use not constitutive of a diagnosis of
abuse or dependence. Furthermore, any acute episode (depressive,
manic, or mixed) within the 8 weeks prior to enrolment, high risk of
suicide or risk of aggression towards others, treatment with any
antidepressant at randomization, treatment with any mood stabi-
lizer other than lithium/valproate/lamotrigine at randomization,

Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
Adjunctive quetiapine for subthreshold bipolar symptoms
treatment with any oral antipsychotic drug at randomization, or
administration of a long acting antipsychotic medication within one
dosing interval prior to randomization. Further exclusion criteria
include the treatment with P450-3A4 cytochrome inhibitors in the
14 days prior to inclusion, including ketoconazole, itraconazole,
fluconazole, erythromycin, clarithromycin, fluvoxamine, indinavir,
nelfinavir, ritonavir and saquinavir, treatment with P450-3A4 cyto-
chrome inducers in the 14 days prior to inclusion, including
phenytoin, carbamazepine, barbiturates, rifampicin, St. John's
wort, and glucocorticoids, having any contraindication to the use
of quetiapine XR or any medical condition that can affect the
absorption, distribution, metabolism or excretion of the study
treatment. Also, any unstable medical condition or not receiving
appropriate treatment for it in the investigator's opinion (e.g.,
hyperthyroidism, angina pectoris, hypertension…), suffering
unstable diabetes at enrolment or randomization, absolute neutro-
phil count r 1.5  109/L at randomization, non-compliance with
the study plan, and participation in another clinical trial in the four
weeks prior to randomization were considered as exclusion criteria.
2.3. Study medication
As the study tried to address clinically relevant gaps, we aimed to
design the treatment as close as possible to current clinical
practice. The selected dose of quetiapine XR (range, 300–600 mg/
d) is consistent with the investigated dose in adults with acute
bipolar depression (Suppes et al., 2010; Calabrese et al., 2005;
Thase et al., 2006). Patients were randomly assigned as outpatients
to receive in a 1:1 ratio either quetiapine XR or placebo once daily
in the evening.
Doses of study medication were titrated from 50 to 100 mg/d
increments, starting at 50 mg/d on day 1, 100 mg/d on day 2,
200 mg/d on day 3, and to a maximum of 300 mg/d on Day 4. From
day 4 to the end of the study, a flexible dose of quetiapine XR from
300 to 600 mg/d (at investigator judgment) was administered. If
unacceptable side effects occurred, investigators had the possibility
to reduce the study medication dose within the range of 150–
300 mg/d. If a 150 mg/d dose was not tolerable, the patient was
withdrawn from the study.
Concomitant treatment with benzodiazepines (equivalent doses
of lorazepam 1–3 mg/d orally) or hypnotic (equivalent doses of
zolpidem 5–10 mg/d orally) was allowed only if prescribed before
trial inclusion and at stable doses during the study. No other
psychotropic drugs were permitted. Other treatment in relation
to general medical care was also allowed at investigator´s
judgment.
2.4. Efficacy outcomes
Clinical assessments of efficacy and safety were conducted at
baseline and weekly intervals thereafter.
The primary outcome was measured by differences between
the study drug and placebo in the change from baseline to week
6 on the Montgomery-Åsberg Depression Rating Scale (MADRS)
(Montgomery and Asberg, 1979).
Secondary efficacy outcomes were the mean change from base-
line to week 6 on the Young Mania Rating Scale (YMRS) (Young et al.,
1978), the 5-item Hamilton Depression Rating Scale (HDRS-5)
(González-Pinto et al., 2009) and the Clinical Global Impression
for Bipolar Disorder (CGI-BD) (Spearing et al., 1997). The percen-
tage of patients with a reduction in the total score of the MADRSo8
and the YMRSo8 (Tohen et al., 2009) maintained until the end of
each follow-up visit (weeks 2, 6 and 12) in all treatment groups was
also assessed. Syndromic remission was defined in depression as
absence of sadness and/or anhedonia and a CGI43 in no more than
2 of the 7 core DSM-IV criteria and in mania as CGIo2 in DSM-IV A
criteria, any DSM-IV B criteria with CGI43 and o more than 2 DSM-IV
Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
3
B criteria=3. This was evaluated in each follow-up visits (weeks 2,
6 and 12) in both treatment groups. Finally, early improvement on
subthreshold depressive symptoms was defined as a reduction of at
least the 20% of the total MADRS score from baseline to visit
performed in week 2 in all treatment groups (Kemp et al., 2011).
2.5. Functioning measures
Level of functioning was assessed as a secondary outcome as the
mean change from baseline to visits performed in weeks 6 and 12,
according to different assessment tools: The Global Assessment of
Functioning (GAF) (American Psychiatric Association, 2000), the
Functioning Assessment Short Test (FAST) (Rosa et al., 2007), the
quality of life questionnaire in relation to health status “Euroqol”
(EQ-5D) (Badia et al., 1999), and the TOlerability and quality Of Life
(TOOL) (Lindström et al., 2009). Achieving functional remission,
defined as the percentage of patients with a score reduction of the
FASTo11 (Rosa et al., 2009) from baseline to visits performed in
weeks 6 and 12, was also evaluated.
2.6. Safety and tolerability
Adverse events (AEs) were classified using the Medical Dictionary for
Regulatory Activities (MedDRA) system of nomenclature. Incidences
and withdrawals due to AEs and serious adverse events (SAEs) were
recorded. AEs assessed were diabetes mellitus, suicidality, extra-
pyramidal-related AEs, QT prolongation, somnolence, and neutro-
penia/agranulocytosis. The Simpson Angus Scale (SAS) (Simpson and
Angus, 1970) and Barnes Akathisia Rating Scale (BARS) (Barnes 1989)
scores from baseline to week 8 were used to evaluate extrapyr-
amidal-related AEs. Suicidality was assessed using the Columbia-
Suicide Rating Scale (C-SSRS) (Posner et al., 2007, 2011). Changes
from baseline were recorded for clinical laboratory parameters,
electrocardiograms, vital signs, and weight. Patients were
requested to fast for 8 h before samples were drawn.
2.7. Statistical analysis
The demographic and baseline clinical variables were analyzed
descriptively by treatment group and the total population. For
continuous variables the mean, median, standard, maximum and
minimum deviation was calculated. Discrete and categorical vari-
ables were analyzed by analysis of absolute and relative frequen-
cies. Baseline characteristics of the treatment groups were
compared in order to determine allocation equipoise.
Efficacy analysis of the primary and secondary outcomes was
performed with data obtained from the intent to treat population
(ITT). Patients receiving at least one dose of the trial treatment
(quetiapine XR or placebo) with at least one baseline and one
subsequent visit completed were analyzed. The final ITT population
was 32 patients (16 treated with placebo and 16 with quetiapine
XR). The primary analysis of the mean change from baseline in the
MADRS tested the superiority of quetiapine in the ITT population
using analysis of covariance (ANCOVA) and last observation carried
forward (LOCF) methodology. The baseline MADRS was used as
covariate and included treatment and diagnostic group strata as
fixed effects in the model, with adjustment for multiple compar-
isons. In addition, it was calculated the mean changes of least
squares (LS), the standard error and the confidence interval of 95%
for each treatment group. The difference between the means and
the confidence interval of 95% was used as a measure of the effect
size. Mann-Whitney U test was used to compare MADRS single items
scores from baseline to week 6 between quetiapine and placebo
patients.
Differences in remission and improvement rates between both
treatment groups were analyzed using a Cochran-Mantel Haenszel
4 M. Garriga et al.
chi-square test across diagnostic strata. Statistical analysis of
patient subgroups was estimated using linear mixed models (LMM)
approach. The YMRS, HDRS-5, CGI-BD, GAF, FAST, EQ-ED and TOOL
scores were analyzed with the ANCOVA in the same way that was
conducted in the primary efficacy analyses.
The safety population included all patients who were rando-
mized, performed at least one protocol visit and took at least one
dose of study medication. The final safety population was also 32
patients (16 treated with placebo and 16 with quetiapine XR).
Safety analyses were based on descriptive statistics. Absolute and
relative of each of the treatment groups frequency, risk difference
(RD) and p-values associated with Chi-square Pearson in the
following cases were calculated: patients who experienced at least
one adverse effect, at least one serious adverse event, at least one
adverse event requiring treatment or led to the discontinuation of
the trial, and patients who experienced at least one adverse effect
related to the trial medication.
Statistical analysis was performed using SPSS (version 21). For
the analysis of some variables, we used the software R with R studio
interface (version 0.99.893) and npIntFactRep package (version
1.5). This study was powered at 90% for a two-sided test at α=0.05
for the comparison between quetiapine XR and placebo. P values
are given with four decimal places. Lower values than 0.0001 are
presented as o0.0001.
3. Results
3.1. Patient population
In this pilot study, a total of 35 patients were screened, and
33 were randomized to receive either quetiapine XR once
daily or placebo. In one patient randomization information
was missed. Due to this, investigators decided not to include
this patient in the analysis. A total of 32 patients were the
ITT population and the safety population (16 randomized to
receive quetiapine XR and 16 to receive placebo). Figure 1
shows the enrollment flowchart.
Figure 1 Enrollment flowchart.
Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
Treatment groups were comparable with respect to socio-
demographic and clinical variables at baseline (Table 1).
3.2. Efficacy variables
All efficacy variables were assessed using mean change from
baseline to visits performed at week 2, 6 (primary end-
point), and 12 using LOCF analysis (Table 2).
3.2.1. MADRS scores
MADRS mean change from baseline to week 6 was assessed
as primary outcome between the two treatment groups
(LOCF analysis). The mean changes in MADRS total score
from baseline to week 6 were 2.44 in the quetiapine XR
and + 2.50 placebo group, respectively, with a significantly
greater reduction in MADRS total score among quetiapine XR
patients compared with placebo (F1,30 = 5.985, P =0.021). A
post hoc analysis did not showed time effect (F1,30 = 0.001,
P = 0.973) but a group  time effect was noticed
(F1,30 = 7.118, P= 0.012). In this regard, patients treated
with quetiapine XR had less severity of depressive symptoms
than the placebo group at week 6 when compared to
baseline.
Analyzing each of the single MADRS score items a trend of
scoring lower (subthreshold symptoms) on each of the items
independently of the treatment group was observed. When
comparing item score differences between baseline and
week 6, there was a significantly greater reduction in the
item 2 (“reported sadness”) and 6 (“concentration difficul-
ties”) in those patients treated with quetiapine XR in
comparison with the placebo group (Z = 3.279, r= 0.580,
P = 0.001 and Z= 2.154, r= 0.381, p= 0.031, respectively).
In summary, we found that quetiapine XR shows super-
iority to placebo in reducing depressive subthreshold symp-
toms in the MADRS after 6 weeks of treatment.
Adjunctive quetiapine for subthreshold bipolar symptoms 5

Table 1 Baseline sociodemographic and clinical characteristics (ITT sample, n =32).

Placebo (n=16) Quetiapine XR (n =16) Total (n =32)

Gender, n (%)
□ Female 9 (56.3) 11 (68.8) 20 (62.5)
□ Male 7 (43.8) 5 (31.3) 12 (37.5)
Age (years), mean (SD) 43.19 (10.3) 44.31 (10.1) 43.75 (10.1)

Academic level, n (%)

□ Primary 9 (56.3) 7 (43.8) 16 (50)
□ Secondary 3 (18.8) 6 (37.5) 9 (28.1)
□ University (25.0) 3 (18.8) 7 (21.9)
DSM-IV-TR diagnosis, n (%)
□ BD I 11 (68.8) 10 (62.5) 21 (65.6)
□ BD II 5 (31.3) 6 (37.5) 11 (34.4)

Lats mood state, n (%)

□ Manic 1 (6.3) 3 (18.8) 4 (12.5)
□ Mixed 1 (6.3) 1 (6.3) 2 (6.3)
□ Hypomanic 6 (37.5) 5 (31.3) 11 (34.4)
□ Depressive 8 (50.0) 7 (43.8) 15 (46.9)
Duration of illness (years), mean (SD) 8.64 (7.1) 5.50 (6.9) 6.97 (7.1)
Time since last episode (months), mean (SD) 25.36 (32.1) 17.06 (16.4) 20.93 (24.9)
Psychiatric hospitalizations, mean (SD) 2.00 (2.4) 1.47 (1.8) 1.73 (2.1)

Lifetime suicide attempts, n (%)

□ 0 9 (56.3) 13 (81.3) 22 (68.8)
□ 1 5 (31.3) 1 (6.3) 6 (18.8)
□ 41 1 (6.3) 0 (0.0) 1 (3.1)
□ Unknown 1 (6.3) 2 (12.5) 3 (9.4)

BD: Bipolar Disorder; ITT: Intention To Treat population; SD: standard deviation; XR: extended release.

3.2.2. Rates of symptomatic and syndromic remission
and rates of early improvement of depressive
subthreshold symptoms
We evaluated symptomatic remission (reduction in MADRS
total score o8 and the YMRS o8) maintained until the end of
each follow-up visit (weeks 2, 6 and 12) in both treatment
groups. Rates of symptomatic remission were higher for the
quetiapine XR group than placebo in each evaluated visit but
no statistical significance was achieved: 31.3% (n=5) vs 12.5%
(n=2), OR 3.182 (p=0.213) (week 2), 43.8% (n=7) vs 12.5%
(n=2), OR 5.444 (p=0.062) (week 6), 43.8% (n=7) vs 18.8
(n=3), OR 3.370 (p=0.136) (week 12). In addition, no time
influence was observed between treatment groups.
Furthermore, we tested syndromic remission (in depres-
sion: absence of sadness and/or anhedonia and a CGI43 in
no more than 2 of the 7 core DSM-IV criteria; in mania:
CGIo2 in DSM-IV A criteria, any DSM-IV B criteria with
CGI43 and o more than 2 DSM-IV B criteria = 3) in each
follow-up visits (weeks 2, 6 and 12) and in all treatment
groups: 13.3% (n = 2) vs 18.8% (n = 3), OR 0.6667 (p= 0.683)
(week 2), 0% (n = 0) OR not calculated, p= not calculated
(week 6), 13.3% (n =2) vs 33.3% (n= 5), OR 0.308 (p= 0.208)
(week 12). Moreover, no time influence was observed
between treatment groups.
When evaluating the rates of early improvement of
depressive subthreshold symptoms (reduction of at least
the 20% of the MADRS total score) from baseline to visit
performed in week 2, no statistical differences between
treatment groups were detected: 37.5% (n= 6) vs 25.0%
(n = 4), OR 1.800, p= 0.448.
3.2.3. YMRS sores
The mean change from baseline to week 6 was evaluated as
secondary outcome with the YMRS.
The mean changes in YMRS total score from baseline to
week 6 were 1.00 in the quetiapine XR group and 0.19
placebo group, respectively, with no group (F1,30 = 0.265,
P= 0.610), time (F1,30 = 0.577, P= 0.453) or group  time
effect (F1,30 =1.233, P= 0.276).
3.2.4. HDRS-5 scores
The mean change from baseline to week 6 was evaluated as
secondary outcome with the HDRS-5.
When evaluating the mean changes in HDRS-5 total score
from baseline to week 6, the quetiapine XR group presented a
greater reduction in comparison with the placebo group
treatment ( 1.38 IC95% [ 2.47, 0.28] vs 0.81 IC95%
[0.16, 1.46], respectively). However, no group (F1,30 =0.866,
P=0.360) or time effect (F1,30 =0.881, P=0.355) was found,
being significant the interaction group  time (F1,30 =13.325,
P=0.001). This results indicate that patients allocated in the
quetiapine XR group presented a significantly lower score at
week 6 compared with the placebo group.

Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
6 M. Garriga et al.

Table 2 Descriptive statistics of the results on the scales at baseline (visit 2) and mean changes from baseline to week 6
(visit 4).

Baseline: Mean (SD) Placebo (n =16) Quetiapine XR (n =16) p-value

Mean change: Mean (SD)
BDI BDII Total BDI BDII Total

MADRS 11.82 (1.40) 12.60 (1.72) 12.06 (1.48) 11.50 (2.01) 12.17 (1.72) 11.75 (1.88)
1.36 (3.63) 1.60 (4.51) 2.5 (5.62) 3.70 (2.59) 1.00 (4.69) 2.44 (4.82) 0.021

YMRS 2.91 (2.70) 3.40 (3.44) 3.06 (2.84) 1.50 (1.72) 6.00 (2.37) 3.19 (2.95)
0.64 (2.84) 1.40 (3.18) 0.19 (2.99) 0.00 (1.81) 2.67 (3.59) 1.00 (3.06) 0.610
HDRS-5 3.36 (1.69) 2.60 (1.52) 3.13 (1.63) 3.00 (1.05) 4.83 (2.32) 3.69 (1.82)
0.64 (1.82) 0.80 (1.66) 0.18 (1.88) 1.50 (0.95) 1.33 (2.42) 1.44 (1.85) 0.360
CGI-BD overall 2.55 (0.93) 3.00 (1.00) 2.69 (0.95) 2.90 (0.88) 3.17 (0.75) 3.00 (0.82)
0.00 (0.99) -0.60 (1.07) 0.19 (0.99) 0.80 (0.94) 0.67 (0.99) 0.75 (0.94) 0.069
GAF 66.18 (9.74) 60.60 (6.88) 64.44 (9.11) 63.10 (9.02) 61.17 (4.83) 62.38 (7.89)
1.09 (10.39) 11.20 (10.15) 2.75 (10.46) 9.80 (11.48) 3.66 (4.86) 7.50 (9.88) 0.196
FAST 24.27 (10.03) 29.20 (6.18) 25.81 (9.10) 29.10 (10.24) 40.83 (10.01) 33.50 (11.43)
3.28 (10.36) 3.00 (9.55) 1.32 (10.95) 6.00 (11.11) 7.16 (7.53) 6.44 (11.25) 0.687

BD, Bipolar Disorder; CGI-BD, Clinical Global Impression for Bipolar Disorder; FAST, Functioning Assessment Short Test; GAF, Global
Assessment of Functioning; HDRS-5, Hamilton Depression Rating Scale-5 items; MADRS, Montgomery-Åsberg Depression Rating Scale;
SD, standard deviation; XR, extended release; YMRS, Young Mania Rating Scale.

In summary, after 6 weeks of treatment, quetiapine XR explaining 12.2% of variance of scores in this domain. The other
appears to be superior to placebo in decreasing depressive FAST sub-domains (occupational, cognitive, economical, inter-
symptoms (according to the HDRS-5 scores). personal relationships and leisure) did not show differences.

3.2.5. CGI-BD scores 3.3.2. GAF scores

The mean change from baseline to week 6 was evaluated as
secondary outcome with the CGI-BD.
The mean changes in the CGI-BD total score as assessed by
the LOCF analysis from baseline to week 6 did not show
differences according to the different treatment groups, time
effect or group  time effect, in all the three subscales
evaluated (CGI-BD mania, CGI-BD depression, and CGI-overall).
At week 6, when analyzing GAF total score there was no
treatment group effect (F1,26 = 1.761, P =0.196) or diagnos-
tic effect (F1,27 = 1.720, P = 0.201). However, a group x
diagnostic effect was seen (F1,26 = 9.546, P= 0.005).
In summary, after 6 weeks of treatment, quetiapine XR
appears to be superior to placebo in BD I patients when
functioning was assessed with GAF scores.

3.3. Functioning measures 3.3.3. EQ-5D scores

An ANCOVA analysis revealed after 6 weeks of treatment no
All functioning variables were assessed using mean change differences between treatment groups (F1,18 =0.004, P=0.952).
from baseline to weeks 2, 6 and 12. No diagnostic or time effects were observed neither
(F1,18 =0.468, P=0.503; F1,18 =0.179, P=0.673; respectively).

3.3.1. FAST assessment

3.3.4. TOOL scores
Functional remission (proportion of patients with a reduc-
After 6 weeks of treatment, no differences were found
tion of the FAST r11 from baseline to week 6 and 12) did
between quetiapine XR and placebo treatment group
not differ significantly between the different treatment
(F1,18 = 0.016; P= 0.901). Regarding TOOL subscales (dizzi-
groups, despite a higher proportion of quetiapine XR
ness/sickness; concern/discouragement; daily activities;
patients presenting functional remission than the placebo
fatigue/weakness; rigidity/tremors; restlessness; sexual
group at the end of the period study: 0% (n = 0) vs 6.3%
function), no differences associated with treatment group,
(n = 1), OR not calculated (P= not calculated) (week 2), 6.3%
time or group x time effect were found.
(n = 1) vs 6.3% (n = 1), OR 1, P = 1 (week 6), 12.5% (n = 2) vs
6.3% (n =1), OR 2.143 (P = 0.174) (week 12). In addition, no
time influence was observed between treatment groups. 3.4. Safety and tolerability variables
When assessing functioning in terms of FAST total score after
12 weeks of treatment, no group (F1,20 =0.167, P=0.687), no 3.4.1. Weight change
diagnostic (F1,20 =2.016, P=0.171) and no group x diagnosis Weight change from baseline to week 12 was evaluated using a
(F1,20 =2.550, P=0.126) effect was observed. Regarding the LOCF analysis. The mean weight at randomization was 73.98 kg
FAST sub-domains scores, there was a significant group  time (95%CI [64.49, 83.48]) in the quetiapine XR group and 73.93 kg
effect (F2,50 =4.173, P=0.027) in the autonomy sub-domain, (95%CI [65.97, 64.49]) in the placebo patients. After 12 weeks,

Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
Adjunctive quetiapine for subthreshold bipolar symptoms
Table 3 Change in weight, laboratory parameters and vital signs after 12 weeks of treatment (safety population).
Placebo (n =16)
n Mean change
Weight change (kg) 16
Glucose (mg/dL) 16
HbA1c (%) 15
Total Cholesterol (mg/dL) 12
LDL cholesterol (mg/dL) 10
HDL cholesterol (mg/dL) 10
Triglycerides (mg/dL) 12
SBP (mmHg) 16
DBP (mmHg) 16
HR (bpm) 16
DBP, diastolic blood pressure; HbA1C, glycosylated hemoglobin; HDL, high density lipoprotein; HR, heart rate; LDL, low density
lipoprotein; SBR, systolic blood pressure; XR, extended release.
the mean weight gain in the quetiapine XR group was greater
than that in the placebo group (+0.86 kg vs 0.42 kg,
respectively) (Table 3), with a lack of significant group
(F1,30 =0.015, P=0.905) and time effect (F1,30 =0.570,
P=0.456). However, although treatment groups were homo-
geneous at the randomization point (week 2), at week 12 there
was a significant group  time effect (F1,30 =4.483, P=0.036),
where quetiapine XR treated patients had significant weight
gain in comparison with the placebo patients at the end of the
trial. In summary, after 12 weeks of treatment, quetiapine XR
appears to cause more weight gain than placebo (P=0.036).
3.4.2. Adverse events (AE) and serious adverse events
(SAE)
Seventy-four AE were reported, 44 (59%) in the quetiapine XR
group and 30 (41%) in the placebo treated patients. The most
common AEs in the quetiapine XR group were somnolence
(9.1%), increased appetite (6.8%), dry mouth (6.8%) and
dizziness (6.8%). In the placebo group, the most frequent
ones were abdominal pain (6.7%) and constipation (6.7%).
Overall, the most recurrently reported AE was somnolence
(6.8%). No deaths were reported in the quetiapine XR group
because of AE in the present study. The proportion of patients
withdrawing from the study due to an AE was 2 in the
quetiapine XR group and none with placebo (2/16 vs 0/16),
as shown in Figure 1. Overall, at least one AE was reported by
93.8% (15/16) of patients in the quetiapine XR treatment
group and 25.0% (8/16) of the placebo group. In this case, the
risk of suffering at least one AE in the quetiapine XR group is
superior to the placebo (χ21 =7.575, P=0.006). In addition, the
risk of developing at least one AE in the quetiapine XR group is
15 times higher than in the placebo (OR 15, 95%IC [1.58,
142.71]). When studying the presence of at least one AE
related with the study medication, more patients in the
quetiapine XR group, 80% (12/15), than in the placebo,
62.5% (5/8), were found, with no statistical significance
(χ21 =0.829, P=0.621).
3.4.3. Changes in laboratory parameters and vital signs
Following 12 weeks of treatment, the mean change from
baseline in serum glucose levels was similar between
Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
7
Quetiapine XR (n =16)
n Mean change
0.42 16 0.86
0.15 16 2.5
0.18 16 0.01
4.42 13 18.15
1.07 8 2.25
1.67 8 0.38
21.51 11 27.45
6.63 16 1.38
2.18 16 2.08
1.12 16 0.87
treatment groups (Table 3), with no time interaction effect
or group x time effect. However, the shift in glucose levels to
clinical important high values (Z110 mg/dL) at week 12 was
greater in the quetiapine XR group (6%) than in the placebo
(0%). Mean changes in total, high-density lipoprotein (HDL),
low-density lipoprotein (LDL cholesterol) and triglycerides
were similar in both treatment groups with no time interac-
tion or group x time effect (Table 3). At week 12, the
quetiapine XR group showed a higher proportion of patients
with a shift to clinically important values of triglycerides
(Z150 mg/dL) (31.3% vs 12.5%, respectively) and LDL cho-
lesterol (Z180 mg/dL) (25% vs 12.5%, respectively) with
similar values of shift in the total cholesterol levels (37.5%
in both groups).
Regarding vital signs, determinations of blood pressure
and heart rate were similar between treatment groups after
12 weeks of treatment.
4. Discussion
This is the first randomized, parallel-group, placebo con-
trolled study to evaluate the efficacy and safety of extended
release formulation of quetiapine a particular treatment
strategy to improve subthreshold symptoms of bipolar dis-
order (BD). The experimental treatment was the extended
release formulation of quetiapine because of the evidence
supporting its use across full acute episodes and mainte-
nance. The adjunctive design was chosen to be closer to
clinical practice, given that BD patients with subthreshold
symptoms (depressive and manic) are most often already
treated with at least one mood-stabilizer. The trial was
meant to be a pilot, investigator-initiated study funded
through a relatively small grant, and not a pivotal, indus-
try-driven trial. Recruitment was slow and the study was
terminated early for that reason. Nevertheless, the study had
enough statistical power to show some differences between
drug and placebo and particularly on the primary outcome.
Studies on the longitudinal course of BD show that
patients spend much more time suffering from depressive
than manic symptoms (Ketter et al., 2016; Samalin et al.,
2016). Moreover, it has been described that subthreshold
8 M. Garriga et al.
symptoms upon remission have a strong prognostic value in
mood disorders in general (Fava, 1999; Altshuler et al.,
2006; Vieta et al., 2007). In clinical practice, bipolar
patients with persistent residual or subthreshold symptoms
pose a complex clinical dilemma in terms of benefit risk of
adding further medication to their treatment regimes. The
problem is how to effectively address those symptoms
without causing burdensome side effects. For example,
clinicians often face the question on the benefits and risks
of adding an antidepressant to the treatment of BD patients
with subthreshold depressive symptoms, given the risk of
causing a switch into mania (Pacchiarotti et al., 2013;
McGirr et al., 2016; Vieta and Garriga, 2016).
Efficacy in double blind, randomized, controlled trials was
the basis for the licensing of quetiapine in bipolar mania,
bipolar depression, bipolar maintenance and major depres-
sive disorder either as monotherapy or adjunctive to other
medications. Although quetiapine exists in two different
formulations, extended-release (XR) and immediate release
(IR), more scientific evidence exists for quetiapine IR (Kapur
et al., 2000; Vieta et al., 2007; Figueroa et al., 2009).
However, both formulations have become one of the most
commonly prescribed drugs for bipolar patients and are used
across all phases of this disorder (Sanford, 2011; Plosker,
2012). So far, only 8 articles study the efficacy of quetiapine
XR for BD, and none of them focuses on subthreshold
symptoms (Suppes et al., 2010; Cutler et al., 2011;
Riesenberg et al., 2012; Sheehan et al., 2013; Gao et al.,
2014; Kim et al., 2014; Suppes et al., 2014; Li et al., 2016).
Although there have been many studies on the quetiapine IR
in the treatment of patients with BD, the evidence base on
the clinical profile of quetiapine XR is largely incomplete.
In this pilot, innovative study, adjunctive quetiapine XR at a
dose of 300 mg once daily was significantly more effective
than placebo in the treatment of subthreshold depressive
symptoms. Although no other trial has been performed in
subthreshold BD patients with quetiapine XR or any other
drug, our results are consistent with previous BD depression
studies where quetiapine XR (Gao et al., 2015; Li et al., 2016)
and quetiapine IR formulation (Calabrese et al., 2005; Thase
et al., 2006; Thase, 2008; McElroy et al., 2010; Young et al.,
2013) appeared to be superior to placebo in reduction of
MADRS scores. In the same line of our results, Suppes et al.
(2010, 2014) and Li et al. (2016) also showed that quetiapine
XR monotherapy improved core symptoms of depression
analyzing mean change in MADRS total score, concluding that
quetiapine XR 300 mg once daily monotherapy was signifi-
cantly more effective than placebo for treating episodes of
depression in BD I within 8 weeks. Other strategies aimed at
improving subthreshold symptoms include a trial with olanza-
pine (Tohen et al., 2008), which in fact addressed the
treatment to mild-to-moderate mania, rather than residual
symptomatology. Psychosocial interventions targeting sub-
threshold symptoms include a pilot randomized controlled
trial of Eye Movement Desensitization and Reprocessing
therapy in traumatized bipolar patients (Novo et al., 2014)
and secondary analyses from Functional Remediation therapy
(Sanchez-Moreno et al., 2017).
This current study did not find treatment group differ-
ences in terms of secondary outcomes, such as symptomatic
remission, syndromic remission or early improvement of
depressive subthreshold symptoms. It has to keep in mind,
Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
however, that the trial was not powered to detect those
differences, and therefore some caution is necessary in
interpreting those particular results. Previous studies with
quetiapine XR have presented a greater improvement in this
treatment group compared with placebo (Cutler et al.,
2011; Sheehan et al., 2013; Suppes et al., 2014). It has also
to be noticed that our sample is formed with patients
suffering from subthreshold symptoms who score low in
affective severity assessments (both depressive and manic).
Interestingly, patients treated with adjunctive quetiapine
XR at a dose of 300 mg once daily did not show any
statistically significant improvement in subthreshold manic
symptoms when evaluated with the YMRS at week 6. Our
results in this regard are consistent with the profile of
quetiapine in the treatment of bipolar depression
(Calabrese et al., 2005; Thase et al., 2006). However, when
Cutler et al. (2011) evaluated the improvement of manic or
mixed episodes with quetiapine XR monotherapy after a
3-week trial, there was greater improvement from baseline
to study end with quetiapine XR than with placebo on the
YMRS (P= 0.004). It is possible that the dose that was used in
our study was too low to show any effect on YMRS scores.
Quetiapine XR treated patients did not presented differ-
ences in terms on CGI-BD, in concordance with previous
studies of quetiapine XR in BD patients (Suppes et al., 2010;
Cutler et al., 2011; Kim et al., 2014; Li et al., 2016). Other
secondary outcomes also failed to show differences in favor
of quetiapine XR vs placebo, including functioning measures
(GAF, FAST, EQ-5D and TOOL). Again, the study was not
powered for those outcomes and it may be particularly
challenging to prove gains in functional outcome in such
population and within a short period of time.
The presence of AE observed in this study with quetiapine
XR was consistent with the known tolerability profile of
quetiapine in bipolar depression (Calabrese et al., 2005;
Thase et al., 2006; Suppes et al., 2010; Riesenberg et al.,
2012; Suppes et al., 2014; Li et al., 2016). As proposed in
previous trials of quetiapine in bipolar depression
(Calabrese et al., 2005; Thase et al., 2006; Suppes et al.,
2010; Kim et al., 2014; Suppes, 2014; Li et al., 2016), in this
study quetiapine XR 300 mg once daily was not associated
with treatment-emergent mania or hypomania.
The high rates of quetiapine XR compliance show that it was
generally well tolerated. The most common AE was somno-
lence, consistent with quetiapine XR known safety profile
(Meulien et al., 2010; Suppes et al., 2010). Patients treated
with quetiapine XR 300 mg once daily presented greater
weight gain than those treated with placebo. There were no
clinically meaningful changes in the blood glucose or lipid
levels in the present study. It has to be noticed that results in
previous studies have shown contradictories results in this
regard (Vieta et al., 2010; Suppes et al., 2010; Cutler et al.,
2011; Riesenberg et al., 2012). This discrepancy might be the
result of differential environmental and cultural factors, such
as diet, exercise, and lifestyle, as well as the short period of
study and the small sample size.
This study has a number of methodological limitations.
There was an unexpected slow recruitment rate and despite
extending the recruitment period, the study had to be
terminated early for that reason. This resulted in a lack of
power, particularly for secondary outcomes. A majority of
patients (approximately 65.6%) enrolled in this study were
Adjunctive quetiapine for subthreshold bipolar symptoms
patients with BD I thereby limiting the availability of informa-
tion about patients with BD II. While doses of 300 and 600 mg/
d once daily of quetiapine have been shown to be effective,
only a fixed dose of 300 mg/d once daily was evaluated in this
study. Another limiting factor of this study was the absence of
an active comparator. In addition, the present study was
performed in outpatients, with the inherent drawbacks of
potential non-compliance, uncertain fasting status for blood
sampling, and at different times of the day for sampling and
weighing patients. On the other hand, some strengths of the
study include the double-blind randomized design, the repre-
sentative patient population, and the clinical relevance of the
study design and outcomes. Furthermore, the adjunctive
design was chosen to be closer to clinical practice, given that
BD patients with subthreshold symptoms (depressive and
manic) are most often already treated with at least one
mood-stabilizer. A further strength is the fact that quetiapine
was given at a single dose at night, which is consistent with
clinical practice and convenience for the patient.
4.1. Conclusions
The current study found that quetiapine XR 300 mg once
daily adjunctive to mood stabilizers is an effective treatment
for subthreshold symptoms in BD patients, especially in
patients with depressive subthreshold symptoms. Significant
improvements in symptoms were seen after 6 weeks of study
and continued throughout week 12. Treatment with quetia-
pine XR 300 mg/d once daily adjunctive to mood stabilizers
was overall well tolerated, but weight gain was detected.
Despite limited effect size and the short treatment period,
our results are relevant for the routine clinical practice of
psychiatry with outpatients with BD. Our results suggest that
BD patients with persistent depressive symptoms not qualify-
ing for full depressive episodes may benefit from adjunctive
treatment with 300 mg/day of quetiapine XR.
Author disclosures
Dr Vieta has received grants and served as consultant, advisor
or CME speaker for the following entities: AB-Biotics, Actavis,
Allergan, AstraZeneca, Bristol-Myers Squibb, Ferrer, Forest
Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Jans-
sen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier,
Shire, Sunovion, Takeda, Telefónica, the Brain and Behaviour
Foundation, the Spanish Ministry of Science and Innovation
(CIBERSAM), the Seventh European Framework Programme
(ENBREC), and the Stanley Medical Research Institute.
Dr Garriga has received grants and served as consultant or
advisor for the following entities: Ferrer, Lundbeck, Jans-
sen, Instituto de Salud Carlos III, FEDER, and Centro de
Investigación Biomédica en Red de salud Mental (CIBERSAM).
Dr Solé has received grants and served as consultant or
advisor for the following entities: Instituto de Salud Carlos
III and Centro de Investigación Biomédica en Red de salud
Mental (CIBERSAM).
Dr González-Pinto has received grants and served as
consultant, advisor or CME speaker for the following enti-
ties: Eli Lilly, JanssenCilag, Lundbeck, Otsuka, Pfizer, Sanofi-
Aventis, Ferrer, the Spanish Ministry of Science and Innova-
tion (CIBERSAM), and the Basque Government.
Please cite this article as: Garriga, M., et al., Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the
control.... European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.429
9
Dr Selva-Vera has received grants from or acted as a
consultant for the following entities: AstraZeneca, Boehrin-
ger Ingelheim, Servier, Bristol-Myers-Squibb/Otsuka, Jans-
sen-Cilag, Eli-Lilly and Pfizer.
Dr Arranz has served as consultant, advisor or CME speaker
for the following entities: Janssen, Lundbeck and Otsuka.
Dr Amann served as speaker for Janssen, Lundbeck and
Otsuka.
Dr Saiz-Ruiz has been a speaker for and on the advisory
boards for the following entities: Lilly, GlaxoSmithKline,
Lundbeck, Janssen, Servier, and Pfizer and has received
grant/honoraria from Lilly and Astra-Zeneca.
The other authors report no financial relationships with
commercial interests.
Declaration of contribution of each author to
the manuscript
Dr Garriga and Dr Solé: acquisition of data, analysis and
interpretation of data, drafting the article.
Dr González-Pinto, Dr Selva, Dr Arranz, Dr Amann, Dr
Sáiz-Ruiz, Dr Pérez-Blanco: conception and design of the
study, acquisition of data, analysis and interpretation of
data, drafting the article.
Dr Vieta: Conception and design of the study, revising
critically for contents, final approval to the version.
Role of the founding source and
acknowledgements
This study was supported by the Centro de Investigación Biomédica
en Red de Salud Mental (CIBERSAM) (Study D1443L00079) through an
unrestricted grant from Astra Zeneca.
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