K Etter 2016

Authors Accepted Manuscript
Treatment of bipolar disorder: Review of evidence

regarding quetiapine and lithium
Terence A. Ketter, Shefali Miller, Bernardo

DellOsso, Po W. Wang
www.elsevier.com/locate/jad
PII: S0165-0327(15)30772-2
DOI: http://dx.doi.org/10.1016/j.jad.2015.11.002
Reference: JAD7827
To appear in: Journal of Affective Disorders
Received date: 13 August 2015
Revised date: 21 October 2015
Accepted date: 1 November 2015
Cite this article as: Terence A. Ketter, Shefali Miller, Bernardo DellOsso and Po
W. Wang, Treatment of bipolar disorder: Review of evidence regarding
quetiapine and lithium, Journal of Affective Disorders,
http://dx.doi.org/10.1016/j.jad.2015.11.002
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Ketter et al: Review on quetiapine and lithium
MANUSCRIPT
p
Title:
Treatment of bipolar disorder: Review of evidence regarding quetiapine and lithium
Authors:
Terence A. Ketter, M.D.a,*
Shefali Miller, M.D.a
Bernardo DellOsso, M.D.a, b
Po W. Wang, M.D.a
a
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA,
USA.
b
Department of Psychiatry, University of Milan; Fondazione IRCCS CaGranda, Ospedale Maggiore
Policlinico, Milan, Italy.
*Corresponding author:
Terence A Ketter, M.D.
Psychiatry Department
401 Quarry Rd MC
5723 Stanford, CA 94305, USA
Tel: (650) 723-2515
E-mail: tketter@stanford.edu
1
Abstract
Background: Lithium, the prototypical mood stabilizer, and quetiapine, a second-generation
antipsychotic, are widely used acute and maintenance pharmacotherapies for bipolar disorder. The
Clinical Health Outcomes Initiative in Comparative Effectiveness in Bipolar Disorder (Bipolar CHOICE)
study was the first comparative effectiveness assessment of lithium versus quetiapine (in combination
with adjunctive personalized treatment), and found no overall significant differences in efficacy and
safety/tolerability outcomes between lithium and quetiapine. Completion of Bipolar CHOICE offers a
timely opportunity to review the evidence regarding lithium and quetiapine for bipolar disorder.
Methods: Controlled clinical trials and real-world observational studies that included quetiapine and
lithium as monotherapy or as combination therapy were identified by literature search. Selected studies
were reviewed in detail.
Results: Review of the available trials suggested comparable efficacy of quetiapine and lithium in acute
mania, and possibly greater efficacy for quetiapine compared with lithium in acute bipolar depression
and in prevention of recurrent (particularly depressive) episodes. Combination therapy including
quetiapine and lithium was generally more effective than either agent alone in acute mania and bipolar
maintenance, although adding lithium to quetiapine did not increase efficacy in acute bipolar depression.
Safety data for quetiapine and lithium were consistent with the established profiles of the two
treatments.
Limitations: Limitations include those of the available efficacy and effectiveness trial data.
Conclusions: Quetiapine and lithium have overlapping but distinctive roles in different phases of bipolar
disorder, and further studies of these agents (particularly in combination with one another) are
warranted.
Word count: 242 (max. 250)
Keywords: Bipolar disorder, Lithium, Quetiapine, Randomized controlled trial, Real-world practice
2
1. Introduction
Pharmacologic treatment of bipolar disorder (BD) is based on administration of mood stabilizers (lithium,
valproate, carbamazepine, and lamotrigine) and, increasingly, on the administration of second-
generation antipsychotics. The prototypical mood stabilizer, lithium, has remained a first-line agent in
the treatment of acute mania and bipolar maintenance treatment for over 60 years (Curran, Ravindran,
2014; Goodwin, 2009; Grunze et al., 2010; Hirschfeld, 2007; International Consensus Group, 2008;
National Institute for Health and Clinical Excellence, 2006; Suppes et al., 2005; Yatham et al., 2013).
While a vast collection of studies with varying older designs support the efficacy and safety of lithium
(Grof, Muller-Oerlinghausen, 2009), there are few contemporary randomized, controlled studies,
particularly for lithium treatment of the depressive phase of BD (Baldessarini et al., 2010). The second-
generation (atypical) antipsychotics, in contrast to lithium, were introduced more recently in the
treatment of BD, with approvals from the US Food and Drug Administration (FDA) based on efficacy and
safety/tolerability profiles demonstrated in randomized, multicenter, double-blind, placebo-controlled
trials. Among the second-generation antipsychotics, quetiapine in immediate-release (IR) and extended-
release (XR) formulations is the only agent that is FDA-approved and recommended in international
treatment guidelines for all three illness phases acute mania (as monotherapy or adjunctive therapy)
(Bowden et al., 2005; McIntyre et al., 2005; Yatham et al., 2004), acute bipolar depression (as
monotherapy) (Calabrese et al., 2005; Thase et al., 2006), and BD maintenance treatment (as adjunctive
therapy) (Grunze et al., 2009; Grunze et al., 2010; Grunze et al., 2013; National Collaborating Centre for
Mental Health (UK), 2006; Suppes et al., 2009; Vieta et al., 2008; Yatham et al., 2013).
Personalized evidence-based clinical prescribing practice is based on evidence from clinical trials
integrated with real-world experience, individualized according to patient and provider preferences.
Recognizing that clinical trial evidence supporting use of lithium is primarily based on studies with
variable and older methodologies, there have been efforts recently to re-evaluate lithium using current
research approaches (Curran, Ravindran, 2014). An example is the Clinical Health Outcomes Initiative in
Comparative Effectiveness in Bipolar Disorder (Bipolar CHOICE) study, which is the first randomized
comparative effectiveness study of lithium (along with other necessary therapies) under conditions
representative of real-world practice, using quetiapine (along with other necessary pharmacologic
therapies) as the comparator (Nierenberg, 2014). In this study, 482 patients with bipolar I or II disorder
were randomized to 6 months of lithium or quetiapine in addition to other necessary
3
pharmacotherapies, referred to as adjunctive personalized treatment (APT). The Bipolar CHOICE study
incorporated minimal exclusion criteria, to maximize generalizability; flexibly dosed APT medications, to
conform to real-world practice; and used intent-to-treat statistical methodology, consistent with design
principles of comparative effectiveness studies (Nierenberg et al., 2014). The Bipolar CHOICE study failed
to demonstrate any statistically significant overall difference between lithium and quetiapine across
measures of symptomatology, quality of life and functioning, suicidal ideation, behavior, and adverse
events (AEs) (Nierenberg, 2014). The findings of the Bipolar CHOICE study were consistent with lithium
and quetiapine having comparable overall efficacy and safety/tolerability. However, the Bipolar CHOICE
study was not powered to demonstrate non-inferiority between lithium and quetiapine. Non-inferiority
studies require substantially more patients than studies such as Bipolar CHOICE, which was powered to
detect superiority of one agent over another.
Completion of the federally funded Bipolar CHOICE study offers a timely opportunity to review evidence
on the use of lithium and quetiapine in BD. Several important Bipolar CHOICE study design elements
resemble real-world clinical practice with lithium and quetiapine in BD. This article reviews Bipolar
CHOICE, as well as additional studies that may further inform the use of lithium and quetiapine in clinical
practice.
Restriction of analysis to monotherapy patients in Bipolar CHOICE could be considered to be (at least in
part) a comparative effectiveness analog of the proprietary quetiapine manufacturer-funded quetiapine
versus lithium comparative efficacy/tolerability maintenance Trial 144, although the latter study was
enriched for acute quetiapine but not lithium response and tolerability (Weisler et al., 2011). Similarly,
analysis of Bipolar CHOICE restricted to depressed patients taking quetiapine monotherapy could be
considered (at least in part) to be a comparative effectiveness analog of the proprietary quetiapine
manufacturer-funded quetiapine Efficacy of Monotherapy Seroquel in BipOLar DEpressioN
(EMBOLDEN) 52-week comparative efficacy/tolerability extension study in patients with bipolar
depression, although the latter study was enriched for acute quetiapine but not lithium remission and
tolerability (Young et al., 2014). Finally, for the Bipolar CHOICE study, analyses limited to acutely
depressed monotherapy patients in the first 8 weeks, or to acutely manic monotherapy patients in the
first 3 weeks, may represent comparative effectiveness analogs of the proprietary quetiapine
manufacturer-funded quetiapine EMBOLDEN I acute bipolar depression and Trial 105 acute mania
comparative efficacy/tolerability studies, respectively, both of which had lithium active comparator
4
arms (Bowden et al., 2005; Young et al., 2010). It is of note that Bipolar CHOICE did not address the issue
of combining quetiapine with lithium, unlike the proprietary quetiapine manufacturer-funded
quetiapine combination studies for acute mania (Sachs et al., 2004; Yatham et al., 2004; Yatham et al.,
2007), acute bipolar depression (Study 55 [Study code D1443L00055; NCT00883493], manuscript in
preparation), or for bipolar maintenance (Suppes et al., 2009; Vieta et al., 2008), which are also
reviewed in this article.
The current article, therefore, provides a review of evidence of efficacy/tolerability (e.g., registration
studies), comparative efficacy/tolerability (e.g., EMBOLDEN I), as well as comparative effectiveness (e.g.,
Bipolar CHOICE) studies of lithium and quetiapine IR and XR formulations, both as monotherapies and as
components of combination therapy. From this review of the evidence, we offer recommendations to
clinicians on potential relative roles of these agents in patients with different presentations of BD.
Moreover, we discuss future directions for research, with a focus on study design and selection of
patient populations.
2. Methods
All studies reviewed in this paper include lithium and quetiapine therapy arms, either as monotherapy
or as components of combination therapy in BD (Fig. 1). Studies were identified by a comprehensive
literature search that included PubMed, EMBASE, and search engines, using the key words: lithium,
quetiapine, bipolar disorder, mania, and depression. No time periods were stipulated for
exclusion of publications, although all retrieved studies were published or otherwise available between
2001 and 2014. A comprehensive listing of the clinical trials is provided in Tables 1 and 2 and
Supplemental Table 1. Papers were selected for more detailed discussion based on the clinical judgment
of the authors, using criteria of relevance, importance, robustness of data, and relevance to the Bipolar
CHOICE study, as described in the Introduction. Studies were dichotomized into two categories: (1)
those exploring quetiapine versus lithium administered without one another (described in Section 3.1,
which includes the Bipolar CHOICE study); and (2) those assessing quetiapine and lithium administered
with one another (described in Section 3.2, which excludes the Bipolar CHOICE study).
5
3. Results
3.1 QUETIAPINE AND LITHIUM WITHOUT ONE ANOTHER
3.1.1 Clinical trial data
This section presents data on the relative efficacy and safety of lithium and quetiapine in clinical trials
that included both quetiapine and lithium administered without one another in acute or maintenance
treatment. Table 1 summarizes the patient populations, study designs, efficacy, and safety outcomes for
the studies selected (additional studies identified by literature search but not selected for discussion are
included in Supplemental files). Four acute monotherapy studies of 3- to 12-week duration in over 800
adult patients with acute bipolar mania (Bowden et al., 2005; Li et al., 2008) or acute bipolar depression
(Kim et al., 2014; Young et al., 2010) and two studies of bipolar maintenance treatment for up to 104
weeks in over 400 patients (Bobo et al., 2014b; Nierenberg, 2014; Weisler et al., 2011) were selected for
detailed discussion.
The efficacy of lithium or quetiapine for treating symptoms of acute bipolar mania or acute bipolar
depression was analyzed in trials using established rating scales, including the Young Mania Rating Scale
(YMRS) and the Montgomery-sberg Depression Rating Scale (MADRS), with response and remission
evaluated by pre-defined criteria for improvement in rating scale scores (i.e., at least 50% relative
improvement in mood symptoms for response and to no more than an absolute level of mood
symptoms low enough to be consistent with wellness for remission) (Table 1). Additional secondary
efficacy measures are included in Table 1. Maintenance treatment efficacy was evaluated by the
prevention of recurrent mood episodes, which were analyzed by the commonly adopted KaplanMeier
survival statistical technique (Weisler et al., 2011). A variety of parameters were assessed to evaluate
the acute and long-term safety/tolerability profiles of lithium and quetiapine, including overall
incidences of spontaneously reported AEs, extrapyramidal AEs and AE rating scales, weight change,
laboratory parameters, treatment-emergent incidence of the opposite mood pole and discontinuations
due to AEs. In contrast to Weisler et al., 2011, Bipolar CHOICE did not include rates of spontaneously
6
reported AEs, but instead used the Frequency and Intensity of Side Effects Ratings/Global Rating of Side
Effects Burden (FISER/GRSEB) side-effects rating scale (Nierenberg, 2014; Nierenberg et al., 2014).
Selected studies
Bipolar subtype and symptoms. Two of the four selected acute quetiapine or lithium administered
without one another studies included patients with bipolar I and II disorder ((Bowden et al., 2005) and Li
et al., 2008 included patients with bipolar I mania alone). Patients were required to have a current
manic episode and at least one prior manic/mixed episode (Bowden et al., 2005; Li et al., 2008) or a
current depressive episode and at least one prior manic/mixed episode (Kim et al., 2014; Young et al.,
2010) for enrollment in the acute studies. The monotherapy maintenance study included bipolar I
patients experiencing a recent manic, depressive or mixed episode (Weisler et al., 2011), whereas
Bipolar CHOICE included patients with bipolar I or II disorder presenting with manic or depressive
symptoms (Bobo et al., 2014b; Nierenberg, 2014).
Study designs. Three acute studies employed double-blind, randomized designs (Bowden et al., 2005; Li
et al., 2008; Young et al., 2010) while one acute study was open-label (Kim et al., 2014). The acute trials
had study durations of 38 weeks, with the lower and higher parts of this range used in acute mania and
acute bipolar depression studies, respectively. Maintenance Trial 144 included open-label treatment
with quetiapine within the stabilization phase, followed by 104 weeks of double-blind maintenance
treatment with quetiapine, lithium or placebo, in patients who met criteria of achieving MADRS and
YMRS scores of 12 or below for 4 weeks (Weisler et al., 2011). Bipolar CHOICE was a 6-month,
prospective, randomized trial of outpatients with bipolar I or II disorder with or without a history of prior
response to lithium or quetiapine (Nierenberg 2014).
Dosing. Fixed or flexible doses of quetiapine XR or IR at doses of 300 mg/day or 600 mg/day (for
depressive symptoms) or up to 800 mg/day (for manic symptoms) were investigated in the acute
monotherapy studies and in Bipolar CHOICE, using a titration schedule that was generally followed over
1 week to achieve target dose (Bowden et al., 2005; Calabrese et al., 2005; McElroy et al., 2010;
McIntyre et al., 2005; Quetiapine fumarate prescribing information, 2013; Quetiapine fumarate
prescribing information, 2014; Suppes et al., 2010; Thase et al., 2006; Young et al., 2010). Lithium was
titrated to achieve serum levels within the range of 0.6 to 1.4 mEq/L in the acute studies and 0.6 to 1.2
7
mEq/L in Bipolar CHOICE (in the United States Prescribing information, the recommended maximum
lithium serum level is 1.5 mEq/L for acute mania (Lithium citrate tetrahydrate, 2013). Quetiapine was
administered at 300800 mg/day and lithium was started at 600 mgday, increased to 900 mgday at
day 4, and then adjusted to maintain serum levels between 0.6 to 1.2 mEq/L in maintenance Trial 144
(Weisler et al., 2011).
Study outcomes: Efficacy. In the acute mania trials, both quetiapine (IR) and lithium demonstrated
efficacy as monotherapy for improving symptoms assessed by change in YMRS from baseline to day 21
or 28 and response and remission rates, which were significantly higher than with placebo (p<0.05) for
quetiapine and lithium in both selected studies (Bowden et al., 2005; Li et al., 2008). Significant
improvements in mania symptoms with quetiapine or lithium versus placebo were observed from day 7
onward in the one study that provided time course information (Bowden et al., 2005).
In an acute bipolar depression comparative efficacy trial comparing quetiapine, lithium and placebo,
significant superiority compared with placebo (p <0.05) was observed for quetiapine in MADRS total
score change from baseline starting week 1 and maintained until week 8 (Young et al., 2010). In contrast,
lithium did not significantly differ from placebo throughout the 8 weeks of treatment (Young et al.,
2010). When grouped according to bipolar I or II subtype, quetiapine at both 300 mg and 600 mg yielded
numerically greater improvement in MADRS score versus placebo for both dosage groups for the bipolar
II subtype, and this reached statistical significance for both the dosage groups for the bipolar I subtype
(p0.01). In a pooled, post-hoc analysis of acute bipolar depression trials, quetiapine demonstrated
significant improvement in MADRS score versus placebo in bipolar II disorder subtype (Young et al.
2013). The second (randomized, but open and nonplacebo-controlled) acute trial of quetiapine XR and
lithium demonstrated a significant improvement from baseline in depressive symptoms according to
Hamilton Depression Rating Scale (HAM-D) score from week 1 through week 8 for both treatments and
comparable week-8 remission rates for both treatments, but a higher week-8 remission rate for
quetiapine XR compared with lithium (Kim et al., 2014).
In double-blind, head-to-head comparisons, the acute efficacy of quetiapine monotherapy was

comparable or superior to lithium for manic symptoms (Bowden et al., 2005; Li et al., 2008) and
numerically superior to lithium for depressive symptoms (Young et al., 2010), measured by change from
baseline in depression rating scale. Thus, in the selected studies, quetiapine compared with lithium,
8
demonstrated comparable to statistically superior efficacy for acute mania and numerically superior
efficacy for acute bipolar depression.
Maintenance treatment with quetiapine or lithium for up to 104 weeks in Trial 144 significantly reduced
recurrence of any mood episode by 71% and 54%, respectively, versus placebo for patients with bipolar I
disorder (Weisler et al., 2011). In this study, quetiapine was significantly superior to lithium in delaying
time to recurrence of any mood or depressive episode (p<0.01), but did not differ significantly in
delaying time to recurrence of a manic episode. A confounding factor in interpretation of these data is
that Trial 144 selected patients whose mood had been stabilized with quetiapine (rather than lithium)
during the initial open-label mood stabilization phase (Weisler et al., 2011). In addition, the mean
lithium serum concentration (0.63 mEq/L) was at the lower end of the therapeutic range, raising the
possibility that lithium was not dosed to optimize efficacy as supported by post-hoc analysis (Nolen,
Weisler, 2013; Weisler et al., 2011). Nevertheless, the findings of Trial 144 are in agreement with
evidence that lithium provides better prophylactic efficacy against manic than depressive episodes
(Curran, Ravindran, 2014), whereas quetiapine appeared similarly effective in preventing recurrence of
both manic and depressive episodes.
The Bipolar CHOICE study enrolled 482 patients with bipolar I or II disorder who were at least mildly
symptomatic (i.e., Clinical Global Impression-Bipolar [CGI-BP] score 3) and required a change in
pharmacotherapy (Bobo et al., 2014b; Nierenberg, 2014). These patients were randomly assigned to
lithium or quetiapine (both combined with APT) for 6 months to evaluate treatment effectiveness
measured by the Clinical Global Impression-Efficacy Index (CGI-EI), Necessary Clinical Adjustments (NCA),
and other secondary measures of symptoms, behavior, functioning, and quality of life (Nierenberg,
2014). After 6 months of treatment, there were no significant overall differences between the lithium
and quetiapine arms for improvement from baseline in CGI-EI and NCA measures. However, some post-
hoc subgroup treatment differences were noted in the study, namely significantly greater improvement
in CGI-EI score with quetiapine in patients with more severe manic/hypomanic symptoms, plus
significantly fewer NCAs per month with lithium in patients with anxiety (p=0.02).
Thus, in the longer-term trial setting, randomized double-blind monotherapy data suggested greater
efficacy for quetiapine than lithium for the prevention of depressive but not manic episodes, whereas
9
randomized open combination treatment data suggested comparable efficacy for quetiapine and lithium
for the treatment and prevention of both depressive and manic symptoms.
Study outcomes: Safety/Tolerability. Safety/tolerability data for quetiapine and lithium monotherapy in
the selected acute and maintenance studies were consistent with the recognized safety/tolerability
profiles of the two treatments (Curran, Ravindran, 2014; Dando, Keating, 2005; Sanford, Keating, 2012).
Lithium was associated with a relative increase in the incidence of tremor, in both the short- and long-
term when compared with quetiapine, which had placebo-level rates of tremor (Weisler et al., 2011;
Young et al., 2010). Lithium was also associated with elevated rates of thyroid and gastrointestinal (i.e.,
vomiting) adverse effects (Bowden et al., 2005; Li et al., 2008). Patients treated with quetiapine
monotherapy as acute or maintenance treatment experienced elevated rates of sedation, somnolence,
and dry mouth, with a trend for these AEs to reduce in frequency over time (Weisler et al., 2011).
Both quetiapine and lithium were associated with short-term weight gain, which was somewhat less in
patients who received lithium (Bowden et al., 2005; Li et al., 2008; Young et al., 2010). During
maintenance treatment over 104 weeks, mean weight declined with lithium (0.9 kg), while quetiapine
was associated with a small increase in weight (0.6 kg) (Weisler et al., 2011). In the Bipolar CHOICE study,
randomized open-combination treatment data suggested comparable safety/tolerability for quetiapine
and lithium.
3.1.2 Real-world evidence
Published real-world evidence (RWE) on the effectiveness (i.e., efficacy and safety/tolerability
considered in aggregate) of quetiapine and lithium administered without one another is sparse and
generally confined to studies that evaluate prescribing or AE trends, which do not necessarily allow
direct comparisons of quetiapine and lithium (Bond et al., 2010; Choong et al., 2012; Dikeos et al., 2010;
Ketter, Haupt, 2006; Prabhakar et al., 2011; Yumru et al., 2007).
A naturalistic study of 91 patients with bipolar I disorder and 141 patients with bipolar II disorder, with
or without comorbid Axis I disorders, compared the long-term effectiveness of open-label quetiapine
monotherapy with that of lithium, sodium valproate, and lamotrigine monotherapies (Altamura et al.,
2008). Medications were selected by the treating psychiatrist based on clinical judgment. Over 4-year
10
follow-up, lithium and quetiapine monotherapies were similarly effective in preventing recurrence of
depressive episodes. These findings are at variance with those of randomized double-blind
monotherapy in Trial 144, in which quetiapine compared with lithium and placebo significantly delayed
time to depressive episode recurrence (Weisler et al., 2011), but similar to those from the randomized
open-combination therapy Bipolar CHOICE study, where quetiapine and lithium had comparable
effectiveness for the treatment and prevention of depressive symptoms. Importantly, use of lower
mean doses of quetiapine in the naturalistic (214189 mg/day) and Bipolar CHOICE (345171 mg/day)
studies, compared with Trial 144 (546173 mg/day), as well as differences in study designs, may have
contributed to the variable outcomes (Altamura et al., 2008; Nierenberg, 2014).
3.2 QUETIAPINE AND LITHIUM WITH ONE ANOTHER
3.2.1 Clinical trial data
This section reviews the efficacy and safety data from clinical trials of quetiapine and lithium
administered with one another versus other therapies. Table 2 summarizes the study designs and results
of selected acute and maintenance studies of quetiapine and lithium administered with one another
(additional studies identified by literature search but not selected for discussion are included in
Supplemental files). The efficacy and safety measures used to assess quetiapine and lithium
administered with one another were as described in the section describing studies of quetiapine and
lithium administered without one another (Table 1).
Four acute (3- to 12-week) combination therapy studies in samples ranging from approximately 10 to
1000 adult patients (Bourin et al., 2014; Sachs et al., 2004; Yatham et al., 2007) and three maintenance
combination therapy studies in samples ranging from approximately 60 to over 1000 patients (Suppes et
al., 2009; Suppes et al., 2013; Vieta et al., 2008) were selected for detailed discussion. An additional
maintenance study evaluated improvement in alcohol dependence following treatment with the
quetiapine plus lithium combination (Stedman et al., 2010).
11
Selected studies
Bipolar subtype and symptoms. Patients with bipolar I disorder with at least one prior manic/mixed
episode and a current manic or depressive episode were enrolled into two of the acute studies and in
the open-label stabilization phases of the maintenance studies. BD subtype was not specified in two
other acute studies. Another trial included patients with a current depressive episode and at least one
prior manic/mixed episode (Study 55, manuscript in preparation). Additionally, one maintenance study
enrolled patients with bipolar I disorder and coexisting alcohol dependence, defined as a minimum of
four or five standard drinks per day for women or men, respectively, on at least 10 of 28 days before
screening (Stedman et al., 2010).
Study design. The acute studies used a double-blind, placebo-controlled design to evaluate quetiapine
added to lithium or divalproex versus placebo plus lithium or divalproex (Sachs et al., 2004; Yatham et
al., 2007) or to evaluate lithium or placebo added to quetiapine XR (Bourin et al., 2014). Patients
included in the acute placebo-controlled studies were assessed to have a lower likelihood of responding
to monotherapy alone, because of the presence of severe manic symptoms (Bourin et al., 2014; Sachs et
al., 2004; Yatham et al., 2007). Study 55 investigated quetiapine XR as monotherapy or in combination
with lithium (Study 55, manuscript in preparation).
Dosing. Quetiapine IR was dosed flexibly up to 800 mg/day according to standard approximately 1-week
titration schedules in the acute mania studies. Study 55 dosed quetiapine XR at 300 mg/day and lithium
at a daily dose adjusted from 600 to 1800 mg/day. Maintenance studies of quetiapine IR/XR
combination therapy adopted the quetiapine IR/XR dosing of the corresponding monotherapy studies
(Suppes et al., 2009; Suppes et al., 2013; Vieta et al., 2008). Similar to the selected monotherapy levels,
lithium as combination therapy was titrated to target serum levels of 0.5 to 1.2 mEq/L in acute and
maintenance studies.
12
Study outcomes: Efficacy. In acute studies, manic symptoms improved significantly after up to 6 weeks
of combination quetiapine IR and lithium/divalproex versus placebo plus lithium/divalproex in one
(Sachs et al., 2004) of two (Sachs et al., 2004; Yatham et al., 2007) studies, as well as in a pooled analysis
of the two studies (Yatham et al., 2004). In addition, quetiapine IR combination therapy with lithium (or
divalproex) significantly alleviated positive activation and aggression symptoms, measured by the
Positive and Negative Syndrome Scale (PANSS), when compared with lithium or divalproex (Sachs et al.,
2004). Moreover, lithium plus quetiapine XR was significantly more efficacious than placebo plus
quetiapine XR on measures of mania and global severity of illness (p<0.001), as well as PANSS-measured
positive symptoms (p=0.003) at day 43 (Bourin et al., 2014). Together, these results indicate benefit
when combining quetiapine with lithium versus either agent alone in acute mania studies. In contrast,
Study 55 (manuscript in preparation), which compared quetiapine XR in combination with lithium with
quetiapine XR monotherapy in acute bipolar depression, found no significant additive benefit with
addition of lithium to quetiapine.
Maintenance studies over at least 104 weeks demonstrated clear superiority for mood outcomes
(reductions in risks of recurrence of any mood, manic, or depressive episodes) with quetiapine plus
lithium/divalproex versus placebo plus lithium/divalproex with (Suppes et al., 2009; Vieta et al., 2008). In
contrast, a maintenance study that evaluated alcohol dependence showed comparable effects for
quetiapine plus lithium/divalproex versus placebo plus lithium/divalproex in reducing the number of
heavy drinking days, alcohol intake, and cigarettes smoked per day (Stedman et al., 2010). Importantly,
the Bipolar CHOICE study did not permit combination of quetiapine with lithium (Nierenberg, 2014).
Study outcomes: Safety/Tolerability. Generally, combination therapy with quetiapine and lithium did
not contribute to yield new types of AEs to the existing safety/tolerability burden in patients with BD
during short-term treatment (Bourin et al., 2014; Potkin et al., 2002; Sachs et al., 2004; Yatham et al.,
2007) or when compared with concurrent placebo and lithium up to 104 weeks of treatment (Suppes et
al., 2009; Vieta et al., 2008); rather, AEs associated with combination treatment were characteristic of
the individual safety profiles of quetiapine and lithium (Curran, Ravindran, 2014; Dando, Keating, 2005;
Sanford, Keating, 2012). However, some shared quetiapine and lithium AEs appeared additive when
quetiapine was combined with lithium. For example, quetiapine IR in combination with lithium resulted
13
in a 5.3 kg gain in weight compared with a 2 kg weight loss with placebo plus lithium over 104 weeks of
treatment (Suppes et al., 2009). Moreover, addition of lithium to quetiapine XR increased the incidence
of tremor approximately three-fold when compared with adding placebo to quetiapine XR (Bourin,
Severus et al. 2014). Combined quetiapine and lithium therapy in Study 55 was associated with greater
frequency of 7% weight gain than quetiapine alone (13.1% vs 7.8%) (Study 55, manuscript in
preparation).
Lithium maintenance treatment appeared to reduce risk of suicidality in bipolar patients (Curran,
Ravindran, 2014). A study of patients with bipolar I disorder and co-occurring alcohol dependence
confirmed the low suicidality risk associated with lithium, but highlighted the potential benefit of
quetiapine plus lithium/divalproex on suicidality risk, as only 0.6% of patients in this group had AEs
potentially related to suicidality compared with 1.6% of placebo plus lithium/divalproex-treated patients
(the statistical significance of this difference was not assessed) (Stedman et al., 2010).
3.2.2 Real-world evidence
There are more published RWE studies of therapy with quetiapine and lithium administered with one
another than of quetiapine and lithium administered without one another, but (as for studies of
quetiapine and lithium administered without one another) these are generally studies that describe
prescribing or AE patterns for multiple treatments and provide limited specific information regarding
administering quetiapine and lithium with one another (Centorrino et al., 2010; Klok et al., 2007; Yumru
et al., 2007).
Four studies evaluated the clinical effectiveness of quetiapine and lithium combination treatment under
real-world conditions (Altamura et al., 2008; Hardoy et al., 2005; Sokolski, Denson, 2003; Suppes et al.,
2007). In a retrospective chart review, 16 veterans with bipolar I disorder and inadequate response to
lithium or divalproex had significant improvements in manic, depressive, and global symptoms when
quetiapine (173 153 mg) was combined with lithium for 30 to 120 days (Sokolski, Denson, 2003). A
naturalistic study of 63 patients with BD (55 with bipolar depression) enrolled in the Stanley Bipolar
Treatment Network used prospective life chart data to examine the maintenance effects of quetiapine
added to standard acute treatment (lithium, valproic acid, or other) (Suppes et al., 2007). Patients
treated with add-on quetiapine for up to 122 149 days had significantly improved mean overall mood
and depression ratings by weeks 10 through 16 compared with baseline (p<0.001). Another naturalistic,
14
4-year study of 232 patients with bipolar I or II disorder, with/without comorbid Axis I disorders,
observed that duration of euthymia was prolonged with quetiapine plus lithium (41.4 2.7 SE months)
compared with quetiapine (24.9 2.7 S.E. months) or lithium (33.1 2.5 S.E. months) without one
another (Altamura et al., 2008). Prevention of mood episode recurrence was evaluated in a fourth study
of 61 patients with BD and inadequate response to standard medications (25 and 14 of 61 patients
received lithium or valproate, respectively). Addition of quetiapine to ongoing treatment for 15.7 (range
642) months significantly reduced the relapse risk for any mood, depressive, or manic episode (p0.05)
(Hardoy et al., 2005).
In summary, available RWE was in general agreement with the randomized controlled trial (RCT)
evidence from maintenance studies, supporting the superior prophylactic efficacy of quetiapine and
lithium administered with one another compared with lithium or quetiapine administered without one
another (Suppes et al., 2009; Vieta et al., 2008).
4. Summary
Review of the available RCT and RWE data presented in this paper permits an overview of the efficacy,
effectiveness, and safety/tolerability of quetiapine versus lithium in different phases of bipolar I or II
disorder. This review was undertaken in the context of the recent Bipolar CHOICE study, a comparative
effectiveness study that did not find significant differences between these pharmacologic therapies for
most outcomes measures in BD.
4.1 Study outcomes and recommendations

Taken together, the evidence from this literature review indicates that quetiapine and lithium
monotherapy may have comparable efficacy for acute treatment and prevention of manic symptoms,
whereas quetiapine may offer superior efficacy for acute treatment and prevention of depressive
symptoms. Furthermore, quetiapine and lithium administered with one another appears superior to
lithium or quetiapine administered without one another for treating acute mania, although adding
lithium to quetiapine is not considered to increase efficacy in acute bipolar depression. In terms of
safety/tolerability, AEs with quetiapine or lithium administered without and with one another in these
studies reflected the known profiles of these two agents specifically, lithium therapy may entail more
tremor, thyroid or gastrointestinal challenges, whereas quetiapine therapy may entail more
15
sedation/somnolence and weight gain challenges and the combination of lithium with quetiapine may
yield additive risks of some AEs (e.g., tremor and weight gain), suggesting that interventions seeking to
avoid differential patient-specific vulnerabilities to specific side effects might yield in a personalized
fashion enhanced safety/tolerability with these agents.
4.2 Study outcomes versus current guidelines

Our conclusions are generally consistent with the treatment recommendations in recent clinical
guidelines for BD. Guidelines developed by experts from existing clinical trial evidence and clinical
experience, commonly recommend lithium or quetiapine monotherapy as first-line treatments for acute
mania (Pfennig et al., 2013; Suppes et al., 2005; Yatham et al., 2013). For partial responders or
nonresponders to monotherapy, lithium in combination with a second-generation antipsychotic is
commonly recommended, while patients with severe acute symptoms are commonly considered
candidates to receive an antipsychotic in combination with lithium or valproate (Goodwin, 2009; Suppes
et al., 2005). In most clinical practice guidelines, quetiapine is either recommended over lithium or
assigned a higher evidence grading for the treatment of acute bipolar depression (Goodwin, 2009;
Grunze et al., 2013; Pfennig et al., 2013). In acutely depressed patients, combination treatment with
lithium and anticonvulsants is recommended in cases of nonresponse to monotherapy or in those
patients with a history of mania (Goodwin, 2009; Grunze et al., 2010). It is worth noting, however, that
in Study 55, adding lithium to quetiapine did not increase efficacy in acute bipolar depression. The
potential roles for antidepressants in bipolar depression remain controversial and recent guidance
suggests that, in multiple clinical scenarios, antidepressant use in bipolar depression should be limited
or avoided (Pacchiarotti et al., 2013).
For maintenance therapy, UK guidelines support quetiapine or lithium as first-line treatments for
patients with predominant mania and quetiapine for patients with predominant depression (Goodwin,
2009). Other guidelines tend to not provide such distinctions based on manic versus depressive
predominant polarity for maintenance treatment, stating that lithium or quetiapine, among others, are
first-line treatment options (Grunze et al., 2013; Pfennig et al., 2013; Yatham et al., 2013). Long-term
combination therapy with lithium, valproate, or an antipsychotic is recommended for monotherapy
nonresponders with predominantly manic burden, while quetiapine or lamotrigine may be added to
long-term treatment when the burden is mainly depressive (Goodwin, 2009).
16
4.3 Physician perspectives on treatment selection

In addition to clinical trial data, both physician and patient experience-based perspectives can influence
treatment selection. Perceptions on relative efficacy have particular significance for physicians when
selecting treatments for patients with BD, while patients perceptions of medication safety/tolerability is
a major influence on acceptance and compliance, particularly for long-term treatment (Hooshmand et
al., 2014; Ketter, Haupt, 2006; Pillarella et al., 2012). A recent study of prescribing trends over 12 years
(20002005 to 20062011) in patients referred to an American specialty bipolar outpatient clinic noted
that quetiapine use had more than doubled (rising significantly from 7.2% to 19.7%), while lithium use
had not significantly changed (dropping non-significantly from 27.6% to 22.7%), by 20062011,
ultimately leaving prevalence of use of these two medications comparable (at approximately one in five
patients each) (Hooshmand et al., 2014). The authors commented that further studies were needed to
explore the inuences of efcacy versus safety/tolerability on prescribing practices for patients with BD.
Another study investigated changes in medication practice for patients with major psychiatric disorders,
including BD, who were taking psychotropics in 2004 or 2009. The results highlighted the increasing use
of combination therapy (including quetiapine and lithium) in 2009 compared with 2004, with apparent
superior symptom improvement, but without apparent increase in AE burden (Centorrino et al., 2010).
Increased awareness of the efficacy advantages of quetiapine, particularly in bipolar depression, may
have contributed to the reported changes in prescribing patterns, while the delayed onset of action (68
weeks) and the potential for safety/tolerability challenges with lithium may have limited its use (Curran,
Ravindran, 2014; Hooshmand et al., 2014).
Nonadherence with long-term treatment remains common among bipolar patients in clinical practice,
increasing the risk of episode recurrence. As shown in the Lithium Moderate Dose Use Study (LiTMUS)
(Sylvia et al., 2014), patient adherence to long-term medication influences the selection of treatment by
physicians. The LiTMUS and Bipolar CHOICE studies utilized the Medication Recommendation Tracking
Form, which the authors advocated as a means to track types of and reasons for medication changes
and to examine clinical decision-making (Reilly-Harrington, Sylvia et al. 2013). Use of such an instrument
could enhance the collaborative nature of clinical decision-making and attention to side effects, both of
which could enhance adherence.
17
4.4 Limitations of our study

Limitations of the current review include those of the available efficacy and effectiveness trial data.
Efficacy studies appear to increase assay sensitivity (ability to detect significant differences between
treatments) at the cost of decreased generalizability (due to assessment of simpler treatment regimens
(e.g. monotherapy or limited two-drug combination therapy) in simpler (e.g. with less comorbidity)
patient cohorts), whereas effectiveness studies appear to increase generalizability (by assessing more
complex treatment regimens (e.g. diverse combinations of two or more drugs) in more complex patient
cohorts) at the cost of decreased assay sensitivity (Friedman et al., 2014).
4.5 Future directions for research

Analyses in the current paper have identified limitations in trial design that could be addressed in
further studies. For example, sample enrichment (i.e., only randomizing patients with sustained
adequate efficacy and safety/tolerability with open quetiapine) in the Trial 144 maintenance study may
have influenced optimal interpretation of the observation of superior efficacy of quetiapine for the
prevention of mood and depressive events versus lithium in that study (Weisler et al., 2011). Use of a
modified design that initiated quetiapine in combination with lithium in the open stabilization
(prerandomization) phase, followed by randomization to monotherapy arms plus placebo and a
combination quetiapine and lithium arm, may at least in part circumvent the potential for the
confounding influence of quetiapine enrichment. A comparable (dual agent stabilization prior to
randomization to one of those agents) design was used in the Bipolar Affective disorder:
Lithium/ANtiConvulsant Evaluation (BALANCE) study of the comparative effectiveness of lithium versus
valproate (Geddes et al., 2010). Further studies incorporating patient populations more representative
of clinical practice, such as patients with varying baseline mood states, complex psychiatric/medical
comorbidities (e.g., anxiety, substance use, and alcohol use disorders), current suicidality, or taking
complex combination therapies at study entry are needed to better inform clinical practice.
4.6 Conclusions
A review of the substantial clinical trial and RWE data for quetiapine and lithium offers the opportunity
to provide treatment recommendations that are relevant to the current clinical management of patients
with BD. These data indicate comparable efficacy and effectiveness for quetiapine and lithium in the
acute treatment and prevention of mania, whereas quetiapine may be superior to lithium as
18
monotherapy in the acute treatment and prevention of bipolar depression. Moreover, quetiapine in
combination with lithium may provide greater benefit than either agent alone in the management of
bipolar patients. Importantly, quetiapine and lithium entail substantively differential adverse effects,
highlighting the importance of individualizing treatment to optimize safety/tolerability.
19
HIGHLIGHTS
Lithium and quetiapine are widely used pharmacologic therapies for the acute and maintenance
treatment of BD
The recent Bipolar CHOICE study was the first comparative effectiveness analysis of lithium
versus quetiapine. Bipolar CHOICE showed no overall differences in efficacy and safety
outcomes between these therapies
The current review of available clinical trials compares lithium and quetiapine administered
without one another as well as in combination BD
These data indicate overlapping but distinctive roles for lithium and quetiapine in different
phases of BD and suggest directions for future research
Role of the funding source: Funding for manuscript preparation was provided by AstraZeneca.
Author disclosures
Terence A. Ketter: Dr. Terence Ketter has financial interests, arrangements, or affiliation with
one or more organizations that could be perceived as real or apparent conflicts of interest. In
the last 3 years, Dr. Ketter has received Grant/Research Support (through Stanford University)
from the Agency for Healthcare Research and Quality, AstraZeneca Pharmaceuticals LP,
Cephalon Inc. (now Teva Pharmaceuticals), Eli Lilly and Company, Pfizer, Inc., and Sunovion
Pharmaceuticals; has served as a Consultant/Advisory Board Member for Allergan, Inc., Avanir
Pharmaceuticals, Depotmed, Forest Pharmaceuticals, Genentech, Janssen Pharmaceuticals,
Merck & Co., Inc., Myriad Genetic Laboratories, Inc., ProPhase, Sunovion Pharmaceuticals, and
Teva Pharmaceuticals; has received Lecture Honoraria (NOT Speakers Bureau payments) from
Abbott Laboratories, Inc, GlaxoSmithKline, Otsuka Pharmaceuticals, Pfizer, Inc., and Sunovion
Pharmaceuticals; and has received Royalties from American Psychiatric Publishing, Inc. In
addition Dr. Ketters spouse is an employee of and stockholder of Janssen Pharmaceuticals.
Shefali Miller: no conflict of interest with the content of the present article to be disclosed.
Bernardo DellOsso: no conflict of interest with the content of the present article to be disclosed.
Over the last 3 years: speakers bureau for Lundbeck; travel support from Angelini and
Cyberonics, Inc.
Po W. Wang: no conflict of interest with the content of the present article to be disclosed.
20
AstraZeneca Pharmaceuticals, LP provided publication support to PAREXEL for preparation of

the current manuscript.
Acknowledgments
The authors thank Bill Wolvey from PAREXEL, who provided medical writing support funded by
AstraZeneca.
Contributors: All authors contributed to the drafting and revision of this manuscript and they approve
the current version for submission.
21
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Friedman, E.S., Iosifescu, D.V., Thase, M.E., Ostacher, M.J., Keyes, M., Rabideau, D., Nierenberg, A.A.,
29
2014. Medication adherence in a comparative effectiveness trial for bipolar disorder. Acta Psychiatr.
Scand. 129, 359-365.
Thase, M.E., Macfadden, W., Weisler, R.H., Chang, W., Paulsson, B., Khan, A., Calabrese, J.R., 2006.
Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled
study (the BOLDER II study). J. Clin. Psychopharmacol. 26, 600-609.
Vieta, E., Suppes, T., Eggens, I., Persson, I., Paulsson, B., Brecher, M., 2008. Efficacy and safety of
quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder
(international trial 126). J. Affect. Disord. 109, 251-263.
Weisler, R.H., Nolen, W.A., Neijber, A., Hellqvist, A., Paulsson, B., 2011. Continuation of quetiapine
versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (trial 144: a
randomized controlled study). J. Clin. Psychiatry 72, 1452-1464.
Yatham, L.N., Kennedy, S.H., Parikh, S.V., Schaffer, A., Beaulieu, S., Alda, M., O'Donovan, C., Macqueen,
G., McIntyre, R.S., Sharma, V., Ravindran, A., Young, L.T., Milev, R., Bond, D.J., Frey, B.N., Goldstein, B.I.,
Lafer, B., Birmaher, B., Ha, K., Nolen, W.A., Berk, M., 2013. Canadian Network for Mood and Anxiety
Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of
CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar. Disord.
15, 1-44.
Yatham, L.N., Paulsson, B., Mullen, J., Vagero, A.M., 2004. Quetiapine versus placebo in combination
with lithium or divalproex for the treatment of bipolar mania. J. Clin. Psychopharmacol. 24, 599-606.
30
Yatham, L.N., Vieta, E., Young, A.H., Moller, H.J., Paulsson, B., Vagero, M., 2007. A double blind,
randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the
treatment of bipolar mania. Int. Clin. Psychopharmacol. 22, 212-220.
Young, A.H., McElroy, S.L., Bauer, M., Philips, N., Chang, W., Olausson, B., Paulsson, B., Brecher, M., 2010.
A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute
phase of bipolar depression (EMBOLDEN I). J. Clin. Psychiatry 71, 150-162.
Young, A.H., McElroy, S.L., Olausson, B., Paulsson, B., 2014. A randomised, placebo-controlled 52-week
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disorder. World J. Biol. Psychiatry 15, 96-112.
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antipsychotics related metabolic syndrome in bipolar patients. J. Affect. Disord. 98, 247-252.
31
Figure Legend
Fig. 1. PRISMA Flow Diagram
HIGHLIGHTS [requested by Journal of Affective Disorders]

Lithium and quetiapine are widely used pharmacologic therapies for the acute and maintenance
treatment of BD
The recent Bipolar CHOICE study was the first comparative effectiveness analysis of lithium
versus quetiapine. Bipolar CHOICE showed no overall differences in efficacy and safety
outcomes between these therapies
The current review of available clinical trials compares lithium and quetiapine administered
without one another as well as in combination BD
These data indicate overlapping but distinctive roles for lithium and quetiapine in different
phases of BD and suggest directions for future research
32
Table 1. Summary of data for selected clinical trials of quetiapine and lithium administered without
one another in patients with bipolar disorder
Study name, Patient population Treatments
publication
details
Efficacy outcomes Safety outcomes
Diagnosis, patient Treatment arms,
#, study design, doses
duration
ACUTE QUETIAPINE AND LITHIUM WITHOUT ONE ANOTHER (MONOTHERAPY): MANIA
Bowden CL, et al. BPI, current Treatment arms: Primary rating scale AEs
episode manic QTP up to 800 Change from baseline to 10%: Dry mouth (QTP up to 800 mg
J Clin Psychiatry and 1 prior mg/day day 21 and day 84 in 24.3%, Li 6.1%, PBO 2.1%), somnolence
2005;66:11121. manic/mixed Li 0.61.4 mEq/L YMRS total: QTP up to (19.6%, 9.2%, 3.1%), weight gain
episode Placebo 800 mg 14.62 and (15.0%, 6.1%, 1.0%), dizziness (12.1%,
(Bowden et al., Aged >18 20.28, Li 15.20 and 7.1%, 2.1%) insomnia (9.3%, 16.3%,
2005)(Trial 105) years QTP initiated at 100 20.76, PBO 6.71 and 20.6%), headache (7.5%, 12.2%, 4.1%),
N=302 mg/day to day 4 (400 9.00 (p<0.001 vs asthenia (6.5%, 4.1%, 1.0%), depression
Double-blind, mg), adjusted to 600 PBO; NS for QTP vs Li) (5.6%, 1.0%, 1.0%), tremor (5.6%,
parallel group, mg/day on day 5 and 18.4%, 4.1%)
placebo- to 800 mg/day on
controlled day 6 (at EPS AEs and rating scales
12-week investigators EPS AEs: QTP up to 800 mg 13.1%, PBO
discretion) 9.3%
BARS and SAS: No significant
differences in change from baseline in
total scores between QTP up to 800 mg
and PBO groups
Weight and 7% weight change

Weight change: QTP up to 800 mg 2.6
kg, Li 0.70 kg, PBO 0.08 kg (p<0.001 for
QTP vs PBO)
7% weight change: Significantly more
frequent in the QTP up to 800 mg group
than in the PBO group at day 84
(p=0.008)
Selected laboratory parameters

Prolactin: QTP up to 800 mg 18.4 g/L,
Li 13.2 g/L, PBO 17.3 g/L
Thyroid-stimulating hormone increase:
QTP up to 800 mg 1.0%, Li 15.7%, PBO
1.1%
Emergence of opposite pole

Treatment-emergent depression
(MADRS score 18 and increase 4 from
baseline on any 2 consecutive post-
baseline assessments or final study
visit): QTP up to 800 mg 5.6%, Li 3.1%,
PBO 8.4% (NS for QTP or Li vs PBO)
Discontinuations due to AEs

Withdrawals due to AEs or concurrent
illness: QTP up to 800 mg 6.5%, Li 6.1%,
PBO 4.1%
33
Secondary rating scales

Change from baseline to
day 21 and day 84 in
CGI-(BP)-I (% much
improved/very much
improved): QTP up to
800 mg 63.6% and
72.0%, Li 64.3% and
72.4%, PBO 30.5%
and 36.8% (p<0.001
for QTP or Li vs PBO)
PANSS total: QTP up
to 800 mg 8.71 and
11.78, Li NR, PBO
2.12 and 1.04
(p<0.001 for QTP or Li
vs PBO)
PANSS positive
subscale: QTP up to
800 mg 4.93 and
6.85, Li NR, PBO 1.55
and 1.48 (p<0.001
PANSS activation
subscale: QTP up to
800 mg 3.69 and
4.97, Li NR, PBO 1.0
and 0.49 (p<0.001
PANSS aggression risk
subscale: QTP up to
800 mg 4.29 and
5.87, Li NR, PBO 1.50
and 1.07 (p<0.001
MADRS: QTP up to
800 mg 1.55 and
1.49, Li NS, PBO 0.05
and +1.21 (p0.001
for QTP vs PBO)
GAS: QTP up to 800
mg 17.96 and 26.35,
Li NR, PBO 5.59 and
9.26 (p<0.001 for QTP
or Li vs PBO)
Response, remission rates

Response at day 21
and day 84 (50%
reduction from
baseline in YMRS total
score): QTP up to 800
mg 53.3% and 72.0%,
Li 53.1% and 75.5%,
PBO 27.4% and 41.1%
vs PBO)
Remission at day 21
and day 84 (YMRS
total score 12): QTP
up to 800 mg 46.7%
and 69.2%, Li 49.0%
and 72.4%, PBO
22.1% and 33.7%
34
vs PBO)
Li H, et al. Curr N=135 QTP up to 800 Primary, secondary rating AEs

BPI, acute mg/day scales Overall: QTP up to 800 mg 78.2%, Li
Med Res Opin manic episode, Li 0.61.2 Change from baseline to 68.8%
2008;24:110.(Li with/without mmol/L day 28 in 5% with QTP up to 800 mg:
psychotic QTP initiated at YMRS total: QTP up to constipation (34.6%), dizziness (15.4%),
et al., 2008) symptoms 100200 mg/day 800 mg 18.2, Li diarrhea (10.3%), alanine
Aged 1865 on day 1, 15.9 (p<0.05 for QTP aminotransferase increase (9.0%),
years increased to and Li vs baseline) palpitations (9.0%), aspartate
4-week 200600 mg/day MADRS total: QTP up aminotransferase increase (7.7%),
Double-blind, on day 4, and to to 800 mg 3.5, Li pharyngolaryngeal pain (6.4%), upper
Li-controlled, max of 800 2.6 (p<0.05 for QTP respiratory tract infection (6.4%), and
randomized, mg/day from day and Li vs baseline) dry mouth (5.1%)
parallel-group 5 PANSS total: QTP up 5% with Li: nausea (16.9%),
to 800 mg 13.5, Li constipation (13.0%), vomiting (13.0%),
10.3 (p<0.05 for QTP nasopharyngitis (11.7%), dizziness
and Li vs baseline) (6.5%), diarrhea (6.5%), and upper
respiratory tract infection (6.5%)
Response at day 28 EPS AEs and rating scales
(50% reduction from EPS AEs: QTP up to 800 mg 5.1%, Li
baseline in YMRS total 6.5%
mg 77.9%, Li 59.7% Weight and 7% weight change
(p=0.013 for QTP vs Weight change: QTP up to 800 mg 1.45
Li) kg, Li 0.25 kg
Remission at day 28 7% weight change: QTP up to 800 mg
(YMRS total score 9.9%, Li 6.5%
12): QTP up to 800
mg 70.1%, Li 48.1% Selected laboratory parameters and
(p=0.007 for QTP vs physical examination
Li) ECG (normal to abnormal at final visit):
Remission at day 28 QTP up to 800 mg 18.0%, Li 19.3%
(YMRS total score 12 Glucose (high level at endpoint): QTP up
+ MADRS total score to 800 mg n=3, Li n=3
8): QTP up to 800
mg 70.1%, Li 48.1% Emergence of opposite pole
(p=0.007 for QTP vs Treatment-emergent depression
Li) (MADRS score 18 and increase 4 from
Remission at day 28 baseline on any 2 consecutive post-
(YMRS total score 8): baseline assessments or final study
QTP up to 800 mg visit): QTP up to 800 mg n=0, Li n=1
51.9%, Li 32.5%
(p=0.015 for QTP vs Discontinuations due to AEs
Li) Withdrawals due to AEs: QTP up to 800
mg n=0, Li n=3
ACUTE QUETIAPINE AND LITHIUM WITHOUT ONE ANOTHER (MONOTHERAPY): DEPRESSION
Kim T, et al. J BPI or BPII, QTP XR 300 Primary rating scale EPS rating scales
current mg/day Sleep efficiency: QTP SAS, BARS, RLSRS: QTP XR 300 mg NR, Li
Affect Disord episode Li 0.8-1.2 XR 300 mg 88.7% (vs NR (NS for QTP and Li vs baseline)
2014;157:33 depression mmol/L 82.0% at baseline), Li
Aged 1865 QTP initiated at 82.4% min (vs 80.9% Emergence of opposite pole
40.(Kim et al., years 50 mg/day on at baseline) (p=0.001 Treatment-emergent mania/hypomania
2014) N=42 day 1, increased and NS for QTP and Li (YMRS score 12 on consecutive
8-week to 100 mg/day vs baseline) assessments): QTP XR 300 mg 0, Li 0
Open-label, on day 3, 200
randomized mg/day on day 5 Secondary rating scales
and to max of Change from baseline to
300 mg/day week 8 in
from day 7 HAM-D-17 total: QTP
XR 300 mg 11.5, Li
17.1 (p<0.001 and
p=0.003 for QTP and
Li vs baseline)
35
CGI-S: QTP XR 300 mg

2.9, Li 3.9 (p=0.001
and p=0.008 for QTP
and Li vs baseline)
PSQI: QTP XR 300 mg
4.8, Li 6.1 (p<0.001
and NS for QTP and Li
vs baseline)
Sleep latency: QTP XR
300 mg 17.8 min, Li
22.8 min (NS for QTP
and Li vs baseline)
WASO: QTP XR 300
mg 39.5 min, Li 86.9
min (p=0.043 and NS
for QTP and Li vs
baseline)

Response at week 8
(50% reduction from
baseline in HAM-D-17
total score): QTP up
to 800 mg 58.3%, Li
35.3% (NS for QTP vs
Li)
Remission at week 8
(HAM-D-17 total
score 7): QTP up to
800 mg 50.0%, Li
11.8% (p=0.038 for
QTP vs Li)
Young AH, et al. J Outpatients Treatment arms: Primary rating scale AEs
with BPI or QTP 300 mg/day Change from baseline to 5%: Somnolence (QTP 300 mg 18.1%,
Clin Psychiatry BPII, major QTP 600 mg/day week 8 in QTP 600 mg 17.6%, Li 8.8%, PBO 3.8%),
2010;71:150 depressive Li 6001800 MADRS total: QTP dry mouth (14.2%, 15.0%, 7.4%, 1.5%),
episode mg/day 300 mg -15.4, QTP dizziness (9.6%, 11.2%, 4.4%, 5.3%),
162.(Young et al., Aged 18 to 65 PBO 600 mg -16.1, Li -13.6, headache (7.3%, 8.6%, 9.6%, 13.7%),
2010) years PBO -11.8 (P<0.001 sedation (6.2%, 5.2%, 0.7%, 1.5%),
N=802 QTP initiated at 50 for QTP doses vs PBO; constipation (4.6%, 7.9%, 2.9%, 2.3%),
(EMBOLDEN I) Double-blind, mg/day to achieve NS for Li vs PBO) nausea (3.8%, 5.6%, 16.9%, 7.6%),
fixed-dose, target dose by day 4 diarrhea (2.3%, 2.6%, 6.6%, 3.8%),
parallel-group (300 mg) or week 1 insomnia (2.3%, 1.1%, 8.8%, 5.3%), and
8-week (600 mg) tremor (0.8%, 3.4%, 5.9%, 0.8%)
Li initiated at 600 EPS AEs and rating scales

mg/day, increased to EPS AEs: QTP 300 mg 5.0%, QTP 600 mg
900 mg/day from day 7.5%, Li 8.1%, PBO 3.8%
4 to 8 SAS: QTP 300 mg 0.1, QTP 600 mg 0.0,
Li 0.1, PBO 0.2
BARS: QTP 300 mg 0.0, QTP 600 mg 0.0,
Li 0.1, PBO 0.0
36

Change from baseline to Weight and 7% weight change
week 8 in Weight change: QTP 300 mg 0.6 kg,
HAM-D total: QTP 300 QTP 600 mg 0.8 kg, Li 0.2 kg, PBO 0.7
mg 14.0, QTP 600 kg
mg 14.2, Li 12.4, 7% weight change: QTP 300 mg 4.6%,
PBO 10.7 (p<0.001 QTP 600 mg 8.3%, Li 2.4%, PBO 3.3%
for QTP doses vs PBO;
NS for Li vs PBO) Selected laboratory parameters and
HAM-D item 1 physical examination
(depressed mood): Glucose: QTP 300 mg 2.2 mg/dL, QTP
QTP 300 mg 1.5, QTP 600 mg 0.4 mg/dL, Li 2.4 mg/dL, PBO
600 mg 1.6, Li 1.4, 1.2 mg/dL
PBO 1.3 (p=0.023 Prolactin: QTP 300 mg 4.1 g/L, QTP
and p=0.001 for QTP 600 mg 3.9 g/L, Li 0.82 g/L, PBO
300 and 600 mg 7.7 g/L
doses vs PBO; NS for Triglycerides: QTP 300 mg 3.5 mg/dL,
Li vs PBO) QTP 600 mg 9.5 mg/dL, Li 2.2 mg/dL,
HAM-A: QTP 300 mg PBO 11.3 mg/dL
9.1, QTP 600 mg Total cholesterol: QTP 300 mg 5.6
9.3, Li 7.7, PBO 6.6 mg/dL, QTP 600 mg 2.2 mg/dL, Li 5.3
(p<0.001 for QTP mg/dL, PBO 8.8 mg/dL
doses vs PBO; NS for
Li vs PBO) Emergence of opposite pole or suicidal
CGI-(BP)-S: QTP 300 ideation
mg 1.5, QTP 600 mg Treatment-emergent mania/hypomania
1.6, Li 1.4, PBO (YMRS score 16 on any 2 consecutive
1.1 (p=0.008 and post-baseline assessments or final study
p=0.002 for QTP 300 visit or AE of mania or hypomania): QTP
and 600 mg vs PBO; 300 mg 4.2%, QTP 600 mg 2.2%, Li
NS for Li vs PBO) 2.2%, PBO 0.8%
SDS: QTP 300 mg Treatment-emergent suicidal ideation
6.9, QTP 600 mg 7.5, (HAM-D item score 3 or an AE of
Li 7.0, PBO 5.3 suicidality, suicidal ideation, suicide
(p=0.041 and p=0.004 attempts, or suicide completion): QTP
for QTP 300 and 600 300 mg 1.9%, QTP 600 mg 1.1%, Li
mg vs PBO; NS for Li 0.7%, PBO 2.3%
vs PBO)
MOS-Cog: QTP 300 Discontinuations due to AEs
mg 5.7, QTP 600 mg Withdrawals due to AEs: QTP 300 mg
6.3, Li 6.0, PBO 4.6 10.4%, QTP 600 mg 13.9%, Li 8.8%, PBO
(p=0.010 for QTP 600 8.4%
mg vs PBO; NS for
QTP 300 mg or Li vs
PBO)

Response at week 8
(50% reduction from
baseline in MADRS
total score): QTP 300
mg 68.6%, QTP 600
mg 69.6%,
Li 62.5%, PBO 55.8%
(p<0.05 and p<0.01
for QTP 300 and 600
mg vs PBO; NS for Li
vs PBO)
Remission at week 8
(MADRS total score
12): QTP 300 mg
69.8%, QTP 600 mg
70.3%, Li 62.5%, PBO
55.0% (p<0.05 and
p<0.01 for QTP doses
37
vs PBO; NS for Li vs
PBO)
MAINTENANCE TREATMENT QUETIAPINE AND LITHIUM WITHOUT ONE ANOTHER
Bobo WV, et al. J BPI or BPII, mildly QTP Primary, secondary rating
symptomatic (CGI- Li scales
Affect Disord BP 3), requiring Change from baseline to
2014;161:30 change in Month 6 in
pharmacotherapy BISS total: no use 29.3,
35.(Bobo et al., N=482 any use 25.0 (p<0.0001
2014a; Bobo et al., Aged 1868 years vs baseline for both
Randomized, groups; p=0.03 between
2014b) multicenter, groups)
(Bipolar CHOICE) comparative BISS mania: no use 4.9,
effectiveness any use 4.3 (p<0.0001 vs
6 months baseline for both groups;
Patients grouped NS between groups)
according to those BISS depression: no use
prescribed (any 9.3, any use 8.0
use) or not (p<0.0001 vs baseline for
prescribed (no use) both groups; NS between
benzodiazepines groups)
BISS anxiety: no use 7.4,
any use 6.4 (p<0.0001 vs
baseline for both groups;
p=0.03 between groups)
BISS irritability: no use
8.5, any use 6.6
(p<0.0001 vs baseline for
both groups; p=0.04
between groups)
CGI-BP: no use 1.6, any
use 1.4 (p<0.0001 vs
p=0.03 between groups)
CGI-EI: no use 1.7, any
use 1.2 (p<0.0001 vs
38

NS between groups)
Nierenberg A. BPI or BPII, mildly QTP + APT Primary, secondary outcomes AEs
symptomatic (CGI- Li + APT CGI-EI (co-primary): NS for AEs: NS for QTP + APT vs Li + APT
Presented at ASCP. BP 3), requiring QTP + APT vs Li + APT
June 2014 change in NCA (co-primary): NS for
pharmacotherapy QTP + APT vs Li + APT
(Nierenberg, 2014) Aged 1868 years Symptoms, CV risk,
N=482 functioning, QoL, suicidal
(Bipolar CHOICE)
Randomized, ideation, behavior: NS for
multicenter, QTP + APT vs Li + APT
comparative
effectiveness
6 months
Weisler RH, et al. J BPI, current or QTP 300800 Primary rating scale AEs
recent episode mg/day Time to recurrence in Overall: QTP (open-label) 70.0%
Clin Psych mania, depression, Li 0.61.2 Any mood event (manic, QTP up to 800 mg 50.2%, Li
2011;72:1452 or mixed (open- mEq/L depressed, or mixed): QTP 59.8%, PBO 56.4%
label stabilization PBO up to 800 mg vs PBO HR AEs (5%; open-label QTP):
64.(Weisler et al., phase) QTP initiated 0.29 95% CI: 0230.38 somnolence (25.6%), dry
2011) MADRS and YMRS at 100 p<0.0001, Li vs PBO HR mouth (13.9%), sedation
score 12 for 4 mg/day to 0.46 95% CI: 0.360.59 (12.8%), dizziness (9.2%),
(Sparcle) consecutive weeks day 4 (400 p<0.0001, QTP up to 800 headache (8.2%), constipation
(entry into mg), adjusted mg vs Li HR 0.66 95% CI: (6.9%), weight increase (5.2%)
maintenance up to 600 0.490.88 p=0.005 AEs (5%; QTP up to 800 mg, Li,
phase) mg/day on PBO): headache (8.9%, 11.5%,
N=2438 (open- day 5 and 7.9%), somnolence (6.7%, 2.6%,
label) between 300 4.2%), insomnia (6.4%, 12.4%,
N=1226 and 800 17.1%), nausea (4.5%, 12.7%,
(randomized) mg/day from 8.2%), tremor (3.0%, 7.4%,
424 weeks (pre- day 6 2.0%), diarrhea (2.7%, 6.2%,
randomization 5.2%), vomiting (2.0%, 11.2%,
phase) 3.0%) s
Up to 104 weeks or
until recurrence of EPS AEs and rating scales
a predefined mood EPS AEs: QTP (open-label) 8.7%
event (maintenance QTP up to 800 mg 4.0%, Li
phase) 9.1%, PBO 4.5%
Double-blind,
randomized, Weight and 7% weight change
placebo-controlled Weight change: QTP (open-
label) 1.7 kg, QTP up to 800 mg
0.6 kg, Li 0.9 kg, PBO 1.5 kg
7% weight change: QTP (open-
label) 16.8% QTP up to 800 mg
10.6%, Li 5.4%, PBO 2.6%
39

and physical examinations
Glucose: QTP (open-label) 0.21
mmol/L, QTP up to 800 mg 0.1
mmol/L, Li 0.2 mmol/L, PBO 0.1
mmol/L
Total cholesterol: QTP (open-
label) 0.2 mmol/L, QTP up to
800 mg 0.2 mmol/L, Li 0.4
mmol/L, PBO 0.4 mmol/L
Triglycerides: QTP (open-label)
0.2 mg/dL, QTP up to 800 mg
0.1 mg/dL, Li 0.3 mg/dL, PBO
0.4 mg/dL
Emergence of opposite pole or

suicidality
AEs related to suicidal
behavior/ideation: QTP up to 800
mg 0.7%, Li 0.7%, PBO 2.0%

Withdrawals due to AEs: QTP
(open-label) 7.0% QTP up to
800 mg 3.5%, Li 4.8%, PBO 3.2%
Time to recurrence in
Manic event: QTP up to
800 mg vs PBO HR 0.29
95% CI: 0.210.40
p<0.0001, Li vs PBO HR
0.37 95% CI: 0.270.53
p<0.0001, QTP up to 800
mg vs Li HR 0.78 95% CI:
0.531.16 NS
Depressive event: QTP up
to 800 mg vs PBO HR 0.30
95% CI: 0.200.44
p<0.001, Li vs PBO HR
0.59 95% CI: 0.420.84
p<0.004, QTP up to 800
mg vs Li HR 0.54 95% CI:
0.350.84 p=0.006
Differences between
treatment groups in
interepisode changes for:
YMRS: QTP up to 800 mg
vs PBO 0.8, Li vs PBO
0.5 (p=0.002 for QTP vs
PBO, p=0.053 for Li vs
PBO)
MADRS: QTP up to 800
mg vs PBO 1.4, Li vs PBO
0.6 (p<0.001 for QTP vs
PBO, NS for Li vs PBO)
CGI-(BP)-S: QTP up to 800
0.1 (p<0.0001 for QTP vs
PBO, NS for Li vs PBO)
CGI-(BP)-GI: QTP up to
800 mg vs PBO 0.3, Li vs
PBO 0.1 (p=0.003 for
QTP vs PBO, NS for Li vs
PBO)
40
PANSS positive subscale:

QTP up to 800 mg vs PBO
0.2, Li vs PBO 0.0 (NS
SDS: QTP up to 800 mg vs
PBO 1.2, Li vs PBO 0.7
(p=0.001 for QTP vs PBO,
NS for Li vs PBO)
MOS-Cog: QTP up to 800
1.5 (p=0.007 for QTP vs
PBO, p<0.001 for Li vs
PBO)
WPAI absenteeism: QTP
up to 800 mg vs PBO 1.3,
Li vs PBO 2.2 (NS for QTP
or Li vs PBO)
WPAI presenteeism: QTP
up to 800 mg vs PBO 6.3,
Li vs PBO 7.0 (P=0.014
for QTP vs PBO, p=0.018
for Li vs PBO)
TMT Part A: QTP up to
PBO 1.4 (NS for QTP or Li
vs PBO)
TMT Part B: QTP up to
PBO 0.1 (NS for QTP or Li
vs PBO)
*Paroxetine-, lithium- or placebo-treated patients with a MADRS and YMRS score 12 in the acute phase received quetiapine 300 mg/day (data
from these patients contributed to the safety analysis only).
Patients treated with quetiapine for mean duration of 122 days.
AE indicates adverse event; APT, adjunctive personalized treatment; BARS, Barnes Akathisia Rating Scale; BISS, Bipolar Inventory of Signs and
Symptoms; BPI, bipolar I disorder; CGI-EI, Clinical Global Impression-Efficacy Index; CGI-S, Clinical Global Impression-Severity of Illness; CI,
confidence interval; ECG, electrocardiogram; EPS, extrapyramidal symptoms; GAS, Global Assessment Scale; HAM-D-17, Hamilton Depression
Rating Scale-17 item; HR, hazard ratio; Li, lithium; MADRS, Montgomery-sberg Depression Rating Scale; MOS-Cog, Medical Outcomes Study-
Cognitive Scale; NCAs, Necessary Clinical Adjustments; NR, not reported; NS, not significant; PANSS, Positive and Negative Syndrome Scale; PBO,
placebo; PSQI, Pittsburgh Sleep Quality Index; QTP, quetiapine; RLSRS, Restless Legs Syndrome Rating Scale; SAS, Simpson Angus Scale; SDS,
Sheehan Disability Scale; TMT, Trail Making Test; YMRS, Young Mania Rating Scale; WASO, Wakefulness After Sleep Onset; WPAI, Work
Productivity and Activity Impairment; XR, extended release.
41
Table 2. Summary of data for selected clinical trials of quetiapine and lithium administered with one
another in patients with bipolar disorder.
Study name, Patient population Treatments
publication details
Efficacy outcomes
Diagnosis, patient Treatment arms, Safety outcomes
#, study design, doses

duration
ACUTE - QUETIAPINE AND LITHIUM COMBINED WITH ONE ANOTHER: MANIA
Bourin M, et al. Int J BPI, most QTP XR up to Primary rating scale AEs
recent episode 800 mg/day Change from baseline to Overall: QTP XR up to 800 mg + Li
Bipolar Disord manic and 1 Li 0.6-1.2 mEq/L day 43 in 63.0%, QTP XR + PBO 48.1%
2014;2:14.(Bourin et manic/mixed PBO YMRS total: QTP XR up Treatment-emergent AEs (5%):
episode in QTP initiated at to 800 mg + Li -22.8, Tremor (QTP XR up to 800 mg + Li
al., 2014) previous 5 300 mg/day on QTP XR + PBO -20.1 15.6%, QTP XR + PBO 4.9%),
years day 1, adjusted (p<0.001 between somnolence (12.7%, 5.5%),
(Trial 003 XR)
Aged 1865 up to 600 groups) constipation (9.2%, 8.7%), dry
years mg/day on day mouth (8.1%, 7.7%), dizziness
N=441 2 and between (6.4%, 4.4%), insomnia (6.4%,
6-week 400 and 800 6.6%), headache (5.2%, 6.0%),
Open-label, mg/day from pyrexia (5.8%, 4.9%)
double-blind, day 3
placebo- EPS AEs and rating scales
controlled, EPS AEs: QTP XR up to 800 mg + Li
parallel-group 16.8%, QTP XR + PBO 6.6%
SAS improved/no
change/worsened: QTP XR up to
800 mg + Li 11.6%/67.1%/15.6%,
QTP XR + PBO 8.2%/75.4%/9.8%
BARS: QTP 300 mg 0.0, QTP 600 mg
0.0, Li 0.1, PBO 0.0

7% weight change: QTP XR up to
800 mg + Li 8.0%, QTP XR + PBO
4.7%
Selected laboratory parameters and

physical examination
Prolactin: QTP XR up to 800 mg + Li
-210.8 mU/L, QTP XR + PBO -116.9
mU/L
Emergence of opposite pole or suicidal

ideation
(not defined): QTP XR up to 800 mg
+ Li 1.2%, QTP XR + PBO 0.5%
Treatment-emergent AEs related to
suicidality: QTP XR up to 800 mg +
Li 0.0%, QTP XR + PBO 0.0%

Withdrawals due to AEs: QTP XR
up to 800 mg + Li 3.5%, QTP XR +
PBO 7.1%
42

day 43 in
CGI-(BP)-S: QTP XR up
to 800 mg + Li -2.5,
QTP XR + PBO -2.2
(p=0.017 between
groups)
CGI-(BP)-C: QTP XR up
to 800 mg + Li 1.7, QTP
XR + PBO 1.9 (p=0.020
between groups)
CGI-(BP)-I: QTP XR up
to 800 mg + Li -15.2,
QTP XR + PBO -13.2
(NS for QTP vs PBO)
PANSS total: QTP XR
up to 800 mg + Li -
19.2, QTP XR + PBO -
15.6 (p<0.001 between
groups)
PANSS activation
subscale: QTP XR up to
800 mg + Li -7.1, QTP
XR + PBO -5.9 (p<0.001
between groups)
PANSS Positive
subscale: QTP XR up to
800 mg + Li -8.1, QTP
XR + PBO -7.0 (p=0.003
between groups)
MADRS total: QTP XR
up to 800 mg + Li -4.8,
QTP XR + PBO -4.1 (NS
between groups)
Response, remission, NNT

Response at day 43
(50% reduction from
score): QTP XR up to
800 mg + Li 79.2%, QTP
XR + PBO 68.2%
(p=0.005 for QTP + Li
vs QTP + PBO)
NNT for response (QTP
XR up to 800 mg + Li vs
QTP XR + PBO): 9
Remission at day 43
(YMRS total score 12):
QTP XR up to 800 mg +
Li 72.3%, QTP XR + PBO
59.7% (p=0.005 for
QTP XR + Li vs QTP +
PBO)
NNT for remission (QTP
XR up to 800 mg + Li vs
QTP XR + PBO): 7.9
43
Sachs G, et al. Bipolar Bipolar I QTP up to 800 Primary scale AEs

disorder, most mg/day Change from baseline to 10%: Somnolence (QTP up to 800
Disord 2004;6:213 recent episode Li 0.71.0 day 21 in mg + Li/DVP 40.0%, PBO + Li/DVP
23.(Sachs et al., 2004) manic and 1 mEq/L YMRS total: QTP up to 10.0%), headache (26.7%, 21.0%),
manic/mixed DVP 50100 800 mg + Li/DVP 13.8, dry mouth (18.9%, 4.0%), asthenia
(Trial 99) episode in g/mL PBO + Li/DVP 9.9 (11.1%, 3.0%), postural
previous 5 PBO (p=0.021 for QTP vs hypotension (11.1%, 3.0%),
years QTP initiated at PBO) dizziness (10.0%, 6.0%)
Aged 18 years 100 mg/day to
N=191 day 4 (400 mg), EPS AEs and rating scales
3-week adjusted up to BARS: QTP up to 800 mg + Li/DVP
Double-blind, 600 mg/day on 0.4, PBO + Li/DVP 0.0
placebo- day 5 and up to SAS: QTP up to 800 mg + Li/DVP
controlled 800 mg/day 1.0, PBO + Li/DVP 0.3
from day 6
Weight: QTP up to 800 mg + Li/DVP
1.6 kg, PBO + Li/DVP 0.4 kg
7% weight change: QTP up to 800
mg + Li/DVP 3.9%, PBO + Li/DVP
1.2% (NS for QTP vs PBO)

Total thyroxine: QTP up to 800 mg
+ Li/DVP 18.5 nmol/L, PBO +
Li/DVP 3.2 nmol/L
Free thyroxine: QTP up to 800 mg +
Li/DVP 0.2 pmol/L, PBO + Li/DVP
0.7 pmol/L
TSH: QTP up to 800 mg + Li/DVP 0.6
mIU/L, PBO + Li/DVP 0.4 mIU/L

(MADRS score 18 and increase 4
from baseline on any 2 consecutive
post-baseline assessments or at last
observation): QTP up to 800 mg +
Li/DVP 17.3%, PBO + Li/DVP 13.5%
(NS for QTP vs PBO)

Withdrawals due to AEs: QTP up to
800 mg + Li/DVP 5.5%, PBO +
Li/DVP 6.0%
day 21 in
YMRS total: QTP up to
800 mg + Li/DVP 13.8,
PBO + Li/DVP 9.9
(p=0.021 for QTP vs
PBO)
CGI-(BP)-S: QTP up to
800 mg + Li/DVP 1.4,
PBO + Li/DVP 0.8
(p=0.001 for QTP vs
PBO)
CGI-(BP)-I: QTP up to
800 mg + Li/DVP
50.6%, PBO + Li/DVP
31.5% (p=0.012 for
QTP vs PBO)
PANSS total: QTP up to
800 mg + Li/DVP 12.5,
44
PBO + Li/DVP 10.1

(NS for QTP vs PBO)
PANSS activation
subscale: QTP up to
800 mg + Li/DVP 4.1,
PBO + Li/DVP 2.8 (NS
for QTP vs PBO)
PANSS supplemental
aggression risk
subscale: QTP up to
800 mg + Li/DVP 4.6,
PBO + Li/DVP 2.8
(p=0.020 for QTP vs
PBO)
MADRS: QTP up to 800
mg + Li/DVP 3.4, PBO
+ Li/DVP 2.8 (NS for
QTP vs PBO)
GAS: QTP up to 800 mg
+ Li/DVP 15.3, PBO +
Li/DVP 11.5 (NS for
QTP vs PBO)

Response at day 21
(50% reduction from
mg + Li/DVP 54.3%,
PBO + Li/DVP 32.6%
(p=0.005 for QTP vs
PBO)
Remission at day 21
(YMRS total score 12):
QTP up to 800 mg +
Li/DVP 45.7%, PBO +
Li/DVP 25.8% (p=0.007
for QTP vs PBO)
Yatham LN, et al. Int BPI, most QTP up to 800 Primary rating scale AEs
recent episode mg/day Change from baseline to 10%: Somnolence (QTP up to 800
Clin Psychopharmacol manic and 1 Li 0.71.0 day 21 and 42 in mg + Li/DVP 28.3%, PBO + Li/DVP
2007;22:212 manic/mixed mEq/L YMRS total: QTP up to 8.7%), dry mouth (19.8%, 1.9%),
episode in DVP 50100 800 mg + Li/DVP 15.2 constipation (10.4%%, 5.8%),
20.(Yatham et al., previous 5 g/mL and 17.2, PBO + weight gain (10.4%, 3.9%)
2007) years PBO Li/DVP 13.2 and 14.3
Aged 18 years QTP initiated at (NS for QTP vs PBO) EPS AEs and rating scales
(Trial 100) N=211 100 mg/day to EPS AEs: QTP up to 800 mg +
6-week day 4 (400 mg), Li/DVP 17.9%, PBO + Li/DVP 28.2%
Double-blind, adjusted up to BARS at day 21 and 42: QTP up to
placebo- 600 mg/day on 800 mg + Li/DVP 0.1 and 0.1,
controlled, day 5 and up to PBO + Li/DVP 0.1 and 0.1
parallel-group 800 mg/day SAS at day 21 and 42: QTP up to
from day 6 800 mg + Li/DVP 0.4 and 0.6,
PBO + Li/DVP 0.4 and 0.5

Weight change: QTP up to 800 mg
+ Li/DVP 1.6 kg, PBO + Li/DVP 0.1
kg
7% weight change: QTP up to 800
mg + Li/DVP 21.0%, PBO + Li/DVP
7.0% (p=0.01 for QTP vs PBO)
45
Treatment-emergent depression at
day 42 (MADRS score 18 and
increase 4 from baseline on any 2
consecutive post-baseline
assessments or at last observation):
QTP up to 800 mg + Li/DVP 6.6%,
PBO + Li/DVP 7.8%

Withdrawals due to AEs: QTP up to
800 mg + Li/DVP 5.8%, PBO +
Li/DVP 2.8%
day 21 and 42 in
CGI-(BP)-S: QTP up to
800 mg + Li/DVP 1.6
and 1.9, PBO + Li/DVP
1.3 and 1.6 (NS for
QTP vs PBO)
CGI-S: QTP up to 800
mg + Li/DVP 1.6 and
1.9, PBO + Li/DVP 1.4
and 1.6 (NS for QTP
vs PBO)
CGI-(BP)-I: QTP up to
800 mg + Li/DVP 64.4%
and 74.0%, PBO +
Li/DVP 54.2% and
58.3% (p=0.01 for QTP
vs PBO)

Response at day 21
and 42 (50%
reduction from
score): QTP (200800
mg) + Li/DVP 56.7%
and 72.1%, PBO +
Li/DVP 50.0% and
57.3% (p=0.03 for QTP
vs PBO)
Remission at day 21
and 42 (YMRS total
score 12): QTP (200
800 mg) + Li/DVP
51.0% and 68.3%, PBO
+ Li/DVP 39.6% and
57.3% (NS for QTP vs
PBO)
ACUTE AND CHRONIC QUETIAPINE AND LITHIUM COMBINED WITH ONE ANOTHER:
DEPRESSION
Study 55 BPI or Treatment arms: Primary rating scales AEs
BPII, QTP XR 300 Change from baseline to Overall: QTP XR 300 mg 36.8%, QTP XR 300 mg +
[manuscript most mg/day week 8 in Li 37.3%
in recent QTP XR 300 MADRS total: QTP XR 5%: Dry mouth (QTP XR 300 mg 34.0%, QTP XR
preparation] episode mg/day + Li (0.8 300 mg 23.7, QTP XR 300 mg + Li 31.5%), somnolence (31.3%, 32.9%),
depressio 1.2 mmol/L) 300 mg + Li 24.3 headache (19.0%, 16.8%), dizziness (10.9%,
n (p=0.378 between 21.5%), nausea (9.5%, 19.5%), tremor (7.5%,
Aged 18 groups) 18.8%), constipation (13.6%, 11.4%), anxiety
QTP initiated at 50
46
to 65 mg/day on day 1, Secondary rating scales (14.3%, 9.4%), diarrhea (9.5%, 8.7%), sedation
years increased to 100 Change from baseline to (6.1%, 7.4%), insomnia (6.8%, 6.0%), weight gain
N=421 mg/day on day 2, 200 week 8 in (5.4%, 7.4%), increased appetite (8.8%, 3.4%),
8-week mg/day on day 3 and HAM-D total: QTP XR tachycardia (5.4%, 4.0%)
(acute to maximum of 300 300 mg 19.1, QTP XR
phase) mg/day from day 4 300 mg + Li 19.7 Weight and 7% weight change
Open- (p<0.001 vs baseline 7% weight change: QTP XR 300 mg 7.8%, QTP
label, for both QTP groups; XR 300 mg + Li 13.1%
parallel- p=0.456 between
group groups) Selected laboratory parameters (% with high values
HAM-D item 1 at end of study)
(depressed mood): Glucose: QTP XR 300 mg 4.6%, QTP XR 300 mg +
QTP XR 300 mg 2.2, Li 6.5%
QTP XR 300 mg + Li Triglycerides: QTP XR 300 mg 14.0%, QTP XR 300
2.4 (p<0.001 vs mg + Li 16.1%
baseline for both QTP Total cholesterol: QTP XR 300 mg 11.5%, QTP XR
groups; p=0.077 300 mg + Li 6.3%
between groups)
HAM-A: QTP XR 300 Emergence of opposite pole
mg 16.0, QTP XR 300 Treatment-emergent mania/hypomania (YMRS
mg + Li 16.6 score 16 on any 2 consecutive weeks or at final
(p<0.001 vs baseline assessment or AE of mania or hypomania): QTP
for both QTP groups; XR 300 mg 2.0%, QTP XR 300 mg + Li 2.1%
p=0.486 between
groups) Discontinuations due to AEs
CGI-S: QTP XR 300 mg Withdrawals due to AEs: QTP XR 300 mg 5.1%, QTP
2.8, QTP XR 300 mg XR 300 mg + Li 5.7%
+ Li 3.0 (p<0.001 vs
baseline for both QTP
doses; p=0.522
between groups)
PSQI: QTP XR 300 mg
3.7, QTP XR 300 mg
+ Li 5.0 (p=0.002 and
p<0.001 vs baseline
for QTP and QTP + Li,
respectively; p=0.621
between groups)
Q-LES-Q-Short Form:
QTP XR 300 mg 17.9,
QTP XR 300 mg + Li
18.8 (p<0.001 vs
baseline for QTP and
QTP + Li; p=0.953
between groups)
SDS: QTP XR 300 mg
14.4, QTP XR 300 mg
+ Li 14.3 (p<0.001 vs
baseline for both QTP
doses; p=0.795
between groups)
TSQM (global
satisfaction): QTP XR
300 mg 26.7, QTP XR
300 mg + Li 34.0
(p<0.001 vs baseline
for both QTP doses)
Response rates
Response (50%
reduction from
baseline in MADRS
total score): QTP XR
300 mg 83.8%, QTP
XR 300 mg + Li 83.6%
47
(p=0.950 between
groups)
MAINTENANCE TREATMENT QUETIAPINE AND LITHIUM COMBINED WITH ONE ANOTHER
Suppes T, et al. Am BPI, most QTP 400 Primary rating scale AEs
recent episode 800 Time to recurrence in Overall: QTP + Li/DVP (open-label) 85.2%,
J Psychiatr mania, mg/day Any mood event QTP up to 800 mg + Li/DVP 78.4%, PBO +
2009;109:477 depression, or Li 0.51.2 (manic, depressed, or Li/DVP 76.7%
mixed mEq/L mixed) : QTP up to 800 AEs (5%; open-label QTP + Li/DVP):
88.(Suppes et al., Aged 18 years DVP 50 mg + Li/DVP vs PBO + sedation (29.5%), somnolence (21.5%),
2009) N=628 125 g/mL Li/DVP HR 0.32 95% dry mouth (20.2%), weight increase
1236 weeks PBO CI: 0.240.42 p<0.0001 (16.3%), tremor (10.9%), headache (9.5%),
(Trial 127) (pre- QTP increased appetite (9.4%), nausea (9.3%),
randomization initiated at dizziness (9.2%), fatigue (6.9%),
phase) 100 constipation (6.6%), vomiting (5.1%)
Up to 104 mg/day to AEs (5%; QTP up to 800 mg + Li/DVP,
weeks or until target dose PBO + Li/DVP): upper respiratory tract
recurrence of a of 600 infection (11.6%, 80%), headache (10.0%,
predefined mg/day on 13.4%), nausea (9.7%, 11.5%), insomnia
mood event day 5; (9.4%, 19.5%), nasopharyngitis (9.0%,
(maintenance flexibly 9.3%), tremor (8.7%, 8.3%), sedation
phase) dosed (7.1%, 1.0%), weight increase (6.8%,
Double-blind, between 2.6%), hypothyroidism (6.5%, 1.3%),
parallel-group, 400 and vomiting (6.1%, 6.1%), back pain (5.8%,
placebo- 800 6.7%), influenza (5.8%, 6.1%), cough
controlled mg/day (5.8%, 3.8%), diarrhea (5.2%, 8.3%),
arthralgia (5.2%, 4.2%)
EPS AEs and rating scales

EPS AEs: QTP + Li/DVP (open-label) 15.5%,
QTP up to 800 mg + Li/DVP 11.0%, PBO +
Li/DVP 9.6%

Weight change: QTP + Li/DVP (open-label)
48
3.1 kg, QTP up to 800 mg + Li/DVP 0.5 kg,

PBO + Li/DVP 2.0 kg
7% weight change: QTP + Li/DVP (open-
label) 23.1%, QTP up to 800 mg + Li/DVP
11.5%, PBO + Li/DVP 3.7%
Selected laboratory parameters and physical

examinations
Glucose: QTP + Li/DVP (open-label) 4.3
mg/dL, QTP up to 800 mg + Li/DVP 6.1
mg/dL, PBO + Li/DVP 0.3 mg/dL
Total cholesterol: QTP + Li/DVP (open-
label) 0.6 mg/dL, QTP up to 800 mg +
Li/DVP 1.5 mg/dL, PBO + Li/DVP 8.8
mg/dL
Triglycerides: QTP + Li/DVP (open-label)
27.2 mg/dL, QTP up to 800 mg + Li/DVP
0.8 mg/dL, PBO + Li/DVP 22.4 mg/dL

Withdrawals due to AEs: QTP + Li/DVP
(open-label) 20.3%, QTP up to 800 mg +
Manic event: QTP up
to 800 mg + Li/DVP vs
PBO + Li/DVP HR 0.30
95% CI: 0.180.49
p<0.0001
Depressive event: QTP
up to 800 mg + Li/DVP
vs PBO + Li/DVP HR
0.33 95% CI: 0.230.48
p<0.0001
Estimated differences
between treatment groups
in interepisode changes
for:
PANSS positive
subscale: 0.2 (NS)
Suppes T, et al. BPI, most QTP 400 Primary rating scale AEs
recent episode 800 Time to recurrence in Overall: QTP + Li (open-label) 81.4%, QTP
Depression Anxiety
mania, mg/day Any mood event + Li (open-label) 80.1%, QTP up to 800 mg
2013;301:1089 depression, or Li 0.51.2 (manic, depressed, or + Li 69.3%, QTP up to 800 mg + DVP
mixed mEq/L mixed): QTP up to 800 63.7%, PBO + Li 70.4%, PBO + DVP 61.3%
98.(Suppes et al.,
Aged 18 years DVP 50 mg + Li vs PBO + Li HR AEs (5%; open-label QTP + Li, QTP +
2013) N=1326 125 g/mL 0.32 95% CI: 0.240.44 DVP): sedation (23.9%, 24.3%),
1236 weeks PBO p<0.001; QTP up to somnolence (17.7%, 20.0%), dry mouth
(pre- QTP 800 mg + DVP vs PBO (16.6%, 17.3%), weight increase (11.0%,
randomization initiated at + DVP HR 0.28 95% CI: 16.7%), tremor (12.6%, 7.8%), dizziness
phase) 100 0.210.37 p<0.001 (9.0%, 8.8%), fatigue (6.6%, 6.6%),
Up to 104 mg/day to constipation (7.7%, 5.5%), vomiting (5.5%,
weeks or until target dose 3.1%)
recurrence of a of 600 AEs (5%; QTP up to 800 mg + Li, QTP up
predefined mg/day on to 800 mg + DVP, PBO + Li, PBO + DVP):
mood event day 5; headache (9.1%, 6.2%, 10.5%, 8.4%),
(maintenance flexibly nasopharyngitis (6.6%, 7.5%, 7.3%, 7.1%),
phase) dosed upper respiratory tract infection (7.7%,
Double-blind, between 5.9%, 4.9%, 3.3%), insomnia (8.0%, 5.4%,
parallel-group, 400 and 19.5%, 14.5%), tremor (5.1%, 6.7%, 6.3%,
placebo- 800 4.1%), nausea (8.8%, 3.8%, 11.8%, 4.6%),
controlled mg/day diarrhea (3.3%, 2.7%, 8.0%, 4.6%)
49
Pooled data EPS AEs and rating scales

from 2 RCTs EPS AEs: QTP + Li (open-label) 17.2%, QTP
+ Li (open-label) 11.6%, QTP up to 800 mg
+ Li 7.3%, QTP up to 800 mg + DVP 8.3%,
PBO + Li 9.1%, PBO + DVP 5.3%

Weight change: QTP + Li (open-label) 2.3
kg, QTP + DVP (open-label) 3.6 kg, QTP up
to 800 mg + Li 0.2 kg, QTP up to 800 mg +
DVP 0.7 kg, PBO + Li 1.9 kg, PBO + DVP
1.9 kg
7% weight change: QTP + Li (open-label)
19.4%, QTP + DVP (open-label) 27.0%,
QTP up to 800 mg + Li 8.7%, QTP up to
800 mg + DVP 9.8%, PBO + Li 2.2%, PBO +
DVP 3.8%

examinations
Glucose: QTP + Li (open-label) 1.5 mg/dL,
QTP + DVP (open-label) 3.2 mg/dL, QTP up
to 800 mg + Li 5.3 mg/dL, QTP up to 800
mg + DVP 6.1 mg/dL, PBO + Li 0.3 mg/dL,
PBO + DVP 0.9 mg/dL
Total cholesterol: QTP + Li (open-label) 1.3
mg/dL, QTP + DVP (open-label) 5.4 mg/dL,
QTP up to 800 mg + Li 2.8 mg/dL, QTP up
to 800 mg + DVP 0.9 mg/dL, PBO + Li 8.6
mg/dL, PBO + DVP 8.4 mg/dL
Triglycerides: QTP + Li (open-label) 16.3
mg/dL, QTP + DVP (open-label) 30.0
mg/dL, QTP up to 800 mg + Li 1.1 mg/dL,
QTP up to 800 mg + DVP 18.3 mg/dL, PBO
+ Li 7.3 mg/dL, PBO + DVP 19.6 mg/dL

Withdrawals due to AEs: QTP + Li (open-
label) 17.5%, QTP + Li (open-label) 17.1%,
QTP up to 800 mg + Li 4.0%, QTP up to
800 mg + DVP 4.8%, PBO + Li 3.5%, PBO +
DVP 2.0%
Manic event: QTP up
to 800 mg + Li vs PBO
+ Li HR 0.26 95% CI:
0.170.41 p<0.001;
QTP up to 800 mg +
DVP vs PBO + DVP HR
0.34 95% CI: 0.220.51
p<0.001
up to 800 mg + Li vs
PBO + Li HR 0.40 95%
CI: 0.260.61 p<0.001;
QTP up to 800 mg +
DVP vs PBO + DVP HR
0.24 95% CI: 0.170.36
p<0.001
Vieta E, et al. J BPI, most QTP 400 Primary rating scale AEs
recent episode 800 Time to recurrence in Overall: QTP up to 800 mg + Li/DVP
mania, mg/day Any mood event 54.8%, PBO + Li/DVP 55.3%
50
Affect Disord depression, or Li 0.51.2 (manic, depressed, or AEs (5%; open-label QTP + Li/DVP):
mixed mEq/L mixed) : QTP up to 800 sedation (16.3%), somnolence (15.3%),
2008;109:251
Aged 18 years DVP 50 mg + Li/DVP vs PBO + dry mouth (11.7%), weight increased
63.(Vieta et al., N=706 125 g/mL Li/DVP HR 0.28 95% (10.6%), dizziness (7.9%), tremor (7.5%),
2008) 1236 weeks PBO CI: 0210.37 p<0.001 headache (7.3%), fatigue (5.9%),
(pre- QTP constipation (5.7%), increased appetite
(Trial 126) randomization initiated at (5.5%), nausea (5.4%), nasopharyngitis
phase) 100 (5.1%)
Up to 104 mg/day to AEs (5%; QTP up to 800 mg + Li/DVP,
weeks or until target dose PBO + Li/DVP): somnolence (5.7%, 2.2%),
recurrence of a of 600 nasopharyngitis (5.4%, 5.4%), headache
predefined mg/day on (5.1%, 5.7%), insomnia (3.9%, 14.2%)
mood event day 5;
(maintenance flexibly EPS AEs and rating scales
phase) dosed EPS AEs: QTP + Li/DVP (open-label) 10.8%,
Double-blind, between QTP up to 800 mg + Li/DVP 5.1%, PBO +
parallel-group, 400 and Li/DVP 4.6%
placebo- 800
controlled mg/day Weight and 7% weight change
Weight change: QTP + Li/DVP (open-label)
2.9 kg, QTP up to 800 mg + Li/DVP 0.5 kg,
PBO + Li/DVP 1.9 kg
7% weight change: QTP + Li/DVP (open-
label) 24.3%, QTP up to 800 mg + Li/DVP
7.4%, PBO + Li/DVP 2.0%

examinations
Glucose: QTP + Li/DVP (open-label) 2.2
mmol/L, QTP up to 800 mg + Li/DVP 4.0
mmol/L, PBO + Li/DVP 0.4 mmol/L
Total cholesterol: QTP + Li/DVP (open-
label) 3.6 mmol/L, QTP up to 800 mg +
Li/DVP 0.5 mmol/L, PBO + Li/DVP 8.0
mmol/L
Triglycerides: QTP + Li/DVP (open-label)
17.9 mg/dL, QTP up to 800 mg + Li/DVP
14.1 mg/dL, PBO + Li/DVP 21.0 mg/dL

Withdrawals due to AEs: QTP + Li/DVP
(open-label) 13.8%, QTP up to 800 mg +
Manic event: QTP up
to 800 mg + Li/DVP vs
PBO + Li/DVP HR 0.30
95% CI: 0.200.44
p<0.001
up to 800 mg + Li/DVP
vs PBO + Li/DVP HR
0.26 95% CI: 0.170.41
p<0.001
Estimated differences
between treatment groups
in interepisode changes
for:
YMRS: 0.9 (p<0.001)
MADRS: 0.7
(p<0.001)
CGI-(BP): 0.1
(p<0.001)
PANSS positive
51
subscale: 0.2
(p<0.001)
SDS: 0.7 (NS)
PGWB: 1.9 (p=0.022)
AE indicates adverse event; BARS, Barnes Akathisia Rating Scale; BPI, bipolar I disorder; CGI-S, Clinical Global Impression-Severity of Illness; CI,
confidence interval; DVP, divalproex; EPS, extrapyramidal symptoms; GAS, Global Assessment Scale; HAM-A, Hamilton Anxiety Rating Scale;
HAM-D-17, Hamilton Depression Rating Scale-17 item; Li, lithium; IMI, imipramine; MADRS, Montgomery-sberg Depression Rating Scale; NNT,
number needed to treat; NS, not significant; PANSS, Positive and Negative Syndrome Scale; PBO, placebo; PGWB, Psychological General Well-
Being scale; PSQI, Pittsburgh Sleep Quality Index; QTP, quetiapine; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; SAS,
Simpson Angus Scale; SDS, Sheehan Disability Scale; TSH, thyroid-stimulating hormone; TSQM, treatment satisfaction questionnaire for
medication; YMRS, Young Mania Rating Scale; XR, extended release.
52
Fig. 1. PRISMA Flow Diagram
Identification
Records identified through Additional records identified

database searching through other sources
(n=30) (n=2)
Records after duplicates removed

(n=32)
Screening
Records screened Records excluded

(n=32) (n=0)
Full-text articles Full-text articles

Eligibility
assessed for eligibility excluded, with reasons

(n=32) (n=0)
Studies included in
qualitative synthesis
Included
(n=32)

K Etter 2016

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Authors Accepted Manuscript

Treatment of bipolar disorder: Review of evidence

Terence A. Ketter, Shefali Miller, Bernardo

Word count: 242 (max. 250)

3.1 QUETIAPINE AND LITHIUM WITHOUT ONE ANOTHER

3.1.1 Clinical trial data

In double-blind, head-to-head comparisons, the acute efficacy of quetiapine monotherapy was

3.1.2 Real-world evidence

3.2 QUETIAPINE AND LITHIUM WITH ONE ANOTHER

3.2.1 Clinical trial data

3.2.2 Real-world evidence

4.1 Study outcomes and recommendations

4.2 Study outcomes versus current guidelines

4.3 Physician perspectives on treatment selection

4.4 Limitations of our study

4.5 Future directions for research

AstraZeneca Pharmaceuticals, LP provided publication support to PAREXEL for preparation of

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Affect. Disord. 161, 30-35.

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on August 10, 2015.

Guideline Number 38 The British Psychological Society and Gaskell, London.

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Quetiapine fumarate (Seroquel) 2013 prescribing information, Wilmington, DE: AstraZeneca

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disorder. World J. Biol. Psychiatry 15, 96-112.

Fig. 1. PRISMA Flow Diagram

HIGHLIGHTS [requested by Journal of Affective Disorders]