Received: 17 May 2017 Revised: 18 October 2017 Accepted: 13 November 2017

DOI: 10.1002/da.22716

RESEARCH ARTICLE

Treatment outcomes of acute bipolar depressive episode

with psychosis

Marco Antonio Caldieraro MD, PhD1,2 Steven Dufour BA1 Louisa G. Sylvia PhD1,3
Keming Gao MD, PhD4 Terence A. Ketter MD5 William V. Bobo MD, MPH6
Samantha Walsh BS1 Jessica Janos BA1 Mauricio Tohen MD, PhD7
Noreen A. Reilly-Harrington PhD1,3 Susan L. McElroy MD8,9 Richard C. Shelton MD10
Charles L. Bowden MD11 Thilo Deckersbach PhD1,3 Andrew A. Nierenberg MD1,3

1 Department of Psychiatry, Massachusetts

General Hospital, Boston, MA, USA
2 Serviço de Psiquiatria, Hospital de Clínicas de
Porto Alegre, Porto Alegre, RS, Brasil
3 Harvard Medical School, Boston, MA, USA
4 Mood Disorders Program, University Hospi-
tals Cleveland Medical Center, Case Western
Reserve University, Cleveland, OH, USA
5 Department of Psychiatry & Behavioral
Sciences, Stanford University School of
Medicine, Stanford, CA, USA
6 Department of Psychiatry and Psychology,
Background: The impact of psychosis on the treatment of bipolar depression is remarkably under-
studied. The primary aim of this study was to compare treatment outcomes of bipolar depressed
individuals with and without psychosis. The secondary aim was to compare the effect of lithium
and quetiapine, each with adjunctive personalized treatments (APTs), in the psychotic subgroup.
Methods: We assessed participants with DSM-IV bipolar depression included in a comparative
effectiveness study of lithium and quetiapine with APTs (the Bipolar CHOICE study). Severity was
assessed by the Bipolar Inventory of Symptoms Scale (BISS) and by the Clinical Global Impres-
sion Scale–Severity–Bipolar Version (CGI-S-BP). Mixed models were used to assess the course of
symptom change, and Cox regression survival analysis was used to assess the time to remission.

Mayo Clinic, Rochester, MN, USA Results: Psychotic features were present in 10.6% (n = 32) of the depressed participants (n = 303).
7 Department of Psychiatry & Behavioral Those with psychotic features had higher scores on the BISS before (75.2 ± 17.6 vs. 54.9 ± 16.3;
Sciences, University of New Mexico Health P < .001) and after (37.2 ± 19.7 vs. 26.3 ± 18.0; P = .003) 6-month treatment. The CGI-S-BP yielded
Sciences Center, Albuquerque, NM, USA
similar results. Participants with and without psychosis had similar course of symptom improve-
8 Lindner Center of HOPE, Mason, OH, USA
ment and similar time to remission. There was no significant difference in the treatment outcomes
9 Deparment of Psychiatry, University of Cincin-
of lithium (n = 11) and quetiapine (n = 21) among the psychotic subgroup.
nati College of Medicine, Cincinnati, OH, USA
10 University of Pittsburgh School of Medicine,
Conclusion: Bipolar depressive episodes with psychotic features are more severe, and compared
Pittsburgh, PA, USA
to nonpsychotic depressions, present a similar course of improvement. Given the small number of
11 Department of Psychiatry, University of Texas
participants presenting psychosis, the lack of statistically significant difference between lithium-
Health Science Center, San Antonio, TX, USA
and quetiapine-based treatment of psychotic bipolar depressive episodes needs replication in a
Correspondence
Marco Antonio Caldieraro, Massachusetts larger sample.
General Hospital, 50 Staniford St #580, Boston,
MA 02114. KEYWORDS
Email: mcaldieraro@hcpa.edu.br
bipolar depression, bipolar disorder, psychosis, psychotic mood disorders, treatment outcome
Funding information
Grant sponsor: Agency for Healthcare
Research and Quality (AHRQ); Grant number:
1R01HS019371-01; Grant sponsor: Dauten
Family Center for Bipolar Treatment Innovation;
Grant sponsor: Coordenação de Aperfeiçoa-
mento de Pessoal de Nível Superior (CAPES);
Grant number: 88881.120434/2016-01.

1 INTRODUCTION disability worldwide (Ferrari et al., 2016). The lifetime prevalence of

psychosis in BD is approximately 65% for bipolar I disorder (BD-I)
Bipolar disorder (BD) affects approximately 2.1% of individuals in and 14–36% for bipolar II disorder (BD-II) (Dell'Osso et al., 2015;
the United States (Merikangas et al., 2007) and is a leading cause of Keck et al., 2003; Pallaskorpi et al., 2015). Psychotic symptoms are

Depress Anxiety. 2018;1–9. wileyonlinelibrary.com/journal/da 

c 2018 Wiley Periodicals, Inc. 1
2 CALDIERARO ET AL .
associated with reduced recovery rates (Solomon et al., 2010), shorter
time to first recurrence (Pallaskorpi et al., 2015; Tohen et al., 2003b),
more hospitalizations (Mazzarini et al., 2010; Ozyildirim, Cakir, &
Yazici, 2010), and neurocognitive deficits (Tsitsipa & Fountoulakis,
2015).
Individuals with BD-I tend to spend three times more days in
depressive than in manic or hypomanic episodes (Judd et al., 2002;
Kupka et al., 2007). This ratio is higher for individuals with BD-II who,
over the course of the disorder, experience depression 50.3% of the
time, whereas hypomania and mixed symptoms are present 1.3 and
2.3% of the time, respectively (Judd et al., 2003).
Despite its importance, bipolar depression remains remarkably
understudied (Fountoulakis et al., 2017). This is particularly true for
psychotic bipolar depression, even though 25% of the individuals with
BD-I experience psychotic symptoms during at least one depressive
episode (Frankland et al., 2015; Goes et al., 2007), and, by definition,
individuals with BD-II only experience psychosis during depressive
(rather than hypomanic) episodes (American Psychiatric Association,
2013). Psychotic features are more frequent and more recurrent in
bipolar depression compared to major depressive disorder (MDD)
(Frankland et al., 2015; Goes et al., 2007; Mitchell et al., 2001;
Zaninotto et al., 2015), and more than a third of individuals who
experience their first psychotic unipolar depressive episode are likely
to switch diagnoses to BD or schizoaffective disorder (Tohen et al.,
2012), particularly if this occurs before age 30 (Akiskal et al., 1995;
Goldberg, Harrow, & Whiteside, 2001). Psychotic features in bipolar
depression are associated with worse suicidality and worse function-
ing (Caldieraro et al., 2017). There is a dearth of information to guide
the treatment of psychotic bipolar depressive episodes (Yatham et al.,
2013). To our knowledge, there are no prospective studies comparing
treatment outcomes between psychotic versus nonpsychotic bipolar
depressive episodes.
1.1 Aims of the study
The primary aim was to assess the treatment outcomes of outpatients
with bipolar depressive episodes with versus without psychotic fea-
tures who participated in the Bipolar Clinical Health Outcomes Initia-
tive in Comparative Effectiveness (Bipolar CHOICE) study. As a sec-
ondary aim, we compared the effectiveness of quetiapine to lithium,
both along with adjunctive personalized treatment (APT) in the psy-
chotic subgroup.
2 METHODS
Participants with a DSM-IV depressive episode at baseline of the Bipo-
lar CHOICE study were included in this secondary analysis. Bipolar
CHOICE was an 11-site, 6-month randomized comparative effective-
ness study comparing lithium (a classic mood stabilizer) to quetiap-
ine (a second-generation antipsychotic) with APTs (or evidence-based,
guideline-informed treatment based on illness course, treatment his-
tory, and current symptomatology) in adult outpatients with BD-I or
BD-II. The APTs were based on the Texas Implementation of Medica-
tion Algorithm (Suppes et al., 2005). The quetiapine + APT group could
receive all available treatments except for lithium and other antipsy-
chotics and the lithium + APT group could receive all available treat-
ments except antipsychotics. Patients were evaluated at baseline and
eight follow-up assessments (weeks 2, 4, 6, 8, 12, 16, 20, and 24). A
detailed description of the study can be found elsewhere (Nierenberg
et al., 2014). The study protocol was approved by the IRB at each site
and participants provided written informed consent before starting
any study-related procedure. The Bipolar CHOICE study was regis-
tered on ClinicalTrials.gov (NCT01331304).
2.1 Participants
Inclusion and exclusion criteria were minimal in the Bipolar CHOICE
study in order to obtain a more diverse and generalizable sample. Eli-
gible patients diagnosed with BD-I or BD-II at any mood state entered
the study with at least mild BD symptoms (Clinical Global Impressions–
Severity–Bipolar Version [CGI-S-BP] overall illness severity score ≥3).
Potential participants were excluded from the study if they had any
contraindication to lithium or quetiapine (e.g., pregnancy, prior hyper-
sensitivity, severe renal disease, lack of treatment response after an
adequate trial), were currently in crisis such that hospitalization or
more acute care was necessary, were currently taking lithium or que-
tiapine, or were unable to comply with study requirements.
2.2 Assessments
2.2.1 Diagnosis and symptom severity
Lifetime and current diagnoses according to Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-
TR) (American Psychiatric Association, 2000), including BD and other
psychiatric comorbidities, were established at the screening visit with
the electronic Mini-International Neuropsychiatric Interview (eMINI-
PLUS), an electronic extended version of a validated structured diag-
nostic interview (Sheehan et al., 1998).
Mood symptom severity was assessed by the Bipolar Inventory of
Symptoms Scale (BISS) (Bowden et al., 2007; Gonzalez et al., 2008) and
the CGI-S-BP (Spearing, Post, Leverich, Brandt, & Nolen, 1997). The
BISS assesses individual mood symptoms in a structured interview that
yields an overall severity score and five distinct domain scores (depres-
sion, mania, anxiety, irritability, and psychosis) (Thompson et al., 2010).
The CGI-S-BP assesses the severity of BD based on the clinician's view
of the patient's global functioning, and provides three scores: overall
illness severity, severity of depression, and severity of mania (Spear-
ing et al., 1997). Remission was defined as a CGI-S-BP Overall Illness
Severity score ≤2, as recommended by the International Society for
BDs (ISBD) Task Force on the Nomenclature of Course and Outcome
in BDs (Tohen et al., 2009).
Items of the psychosis domain of the BISS were used to define the
presence of psychotic symptoms (i.e., items 41-Persecutory Ideas; 42-
Delusions; 43-Hallucinations; and 44-Impaired Insight). Patients were
considered psychotic if a persecutory delusion was present on item
41 (score = 4); a delusion or hallucination was definitely present on
items 42 or 43 (score ≥2); or if a psychotic impairment of insight was
CALDIERARO ET AL .
present on item 44 (i.e., the patient gave a delusional explanation for
the illness—score = 3, or denied it—score = 4).
2.2.2 Treatment effectiveness
To compare effectiveness of lithium + APT versus quetiapine + APT
in the psychotically and nonpsychotically depressed Bipolar CHOICE
study participants, we used the Clinical Global Impression–Efficacy
Index–Bipolar Version (CGI-EI-BP) (Feighner et al., 1983; Nierenberg
et al., 2016). This measure integrates benefit and harms to yield scores
that can be compared across interventions. We defined the CGI-EI-BP
as the difference between the rated benefit and harm; thus, CGI-EI-BP
scores range from –3 (i.e., no benefit, significant harm) to +3 (i.e., sig-
nificant benefit, no harm) (Nierenberg et al., 2016).
2.2.3 Statistical analysis
Data were analyzed using SPSS 20.0 (Chicago, IL). Univariate analyses
were performed using t tests for continuous variables with a normal
distribution and Mann–Whitney U tests for continuous variables with
non-normal distribution. Categorical variables were compared using
chi-square (𝜒 2 ) tests with exact tests when indicated. We used a two-
tailed significance threshold of P < .05, with no correction for multiple
comparisons, due to the exploratory nature of this study.
Differences in the posttreatment scores on BISS total, BISS depres-
sion domain, CGI-S-BP Overall, and CGI-S-BP Depression were
adjusted for treatment group in four separate linear regression models.
In these models, the posttreatment score on the BISS or CGI scale was
the dependent variable whereas the episode type (i.e., psychotic vs.
nonpsychotic) and treatment group (i.e., quetiapine vs. lithium) were
the independent variables. The difference in remission rate of psy-
chotic and nonpsychotic individuals was adjusted in a similar fashion
with a binary logistic model. This model additionally controlled for ini-
tial baseline depression severity (BISS depression domain) as an inde-
pendent variable.
We also examined course of improvement in depressed patients
with versus without psychosis over the full course of the study. First,
group-level changes in BISS Total and BISS depression were assessed
using individual growth curve mixed models for each respective scale,
each of which controlling for randomization and baseline depression
severity. Additionally, Cox regression survival analysis was conducted
to assess between-group differences in remission rates over each indi-
vidual time point. To examine the secondary aim of the study, we per-
formed the same procedures above for the subgroup of depressed
patients with psychosis to compare outcomes between the two treat-
ments (lithium + APT vs. quetiapine + APT).
3 RESULTS
Three hundred and three patients (62.9% of the original 482 Bipo-
lar CHOICE participants) presented with a major depressive episode
at the time of enrollment. Among these depressed patients, BD-I was
more frequent (64.7%; n = 196) than BD-II (35.3%; n = 107), and psy-
chotic features were present in 32 individuals (10.6%). There was no
3
significant difference in age or sex between depressed patients with
psychosis versus without psychosis at enrollment; however, depressed
patients with versus without psychotic features were more frequently
single and unemployed, and had less educational attainment. Psychosis
was also associated with higher rates of comorbid agoraphobia, social
phobia, and generalized anxiety disorder (see Table 1).
3.1 Psychotic versus nonpsychotic depressive
episodes
At baseline, patients with psychotic features had significantly higher
(worse) mean total scores on the BISS total and CGI-S-BP, and on
two depression-specific measures (depression domain of BISS and
CGI-S-BP depression). Both groups showed significant improvement
in overall illness and depression severity scores during the study fol-
low up. After 6 months of treatment, depressed individuals with psy-
chotic symptoms had significantly higher mean overall BISS and CGI
scores, but not BISS depression domain or CGI depression scores,
than nonpsychotic depressed subjects, as shown in Table 2. Differences
between those with and without psychotic features in the posttreat-
ment scores adjusted for treatment group (i.e., lithium and quetiapine)
were similar to those observed in the univariate analysis, and treat-
ment group was not associated with the posttreatment scores.
The remission rate for the nonpsychotic group was significantly
higher than for the psychotic group after 6 months (75% vs. 53%,
P = .04). In a logistic regression model, remission rates were associ-
ated with baseline depression severity (𝛽 = − .075; P < .001), but not
with the presence of psychosis (𝛽 = .459; P = .255) or treatment group
(𝛽 = − .084; P = .740).
Two mixed model regressions controlling for baseline severity com-
pared the course of symptom improvement across the groups over
time. The first model evaluated change in overall BISS score (Fig. 1)
and the second evaluated change in depression domain of the BISS. In
both models, there were significant main effects of group (BISS total:
F = 19.9; P < .001—BISS depression: F = 5.3; P = .021) and time (study
visit) (BISS total: F = 395.4; P < .001—BISS depression: F = 305.1;
P < .001); however, there were no significant group × time interac-
tion effects (BISS total: F = 1.6; P < .198—BISS depression: F = .7;
P = .400). These results indicated that patients with psychotic versus
nonpsychotic depression reported more severe depressive and overall
BD symptoms during the study, but there was no significant difference
in the rates of improvement between the two groups.
Despite differences in remission rates in univariate analyses, the
Cox survival analysis found no statistically significant difference
between the psychotic and nonpsychotic groups (hazard ratio = 1.58;
P = .099). This was unaffected by adjusting for treatment group (hazard
ratio = 1.61; P = .088), consistent with the mixed model analyses.
3.2 Quetiapine- versus lithium-based treatment in
depressive episodes with psychotic features
Of the 32 patients presenting with a psychotic depressive episode,
21 were randomized to the quetiapine + APT group and 11 to the
lithium + APT group. There were no significant differences in mean
4 CALDIERARO ET AL .

TA B L E 1 Characteristics of psychotic and nonpsychotic bipolar depression groups

Psychotic Nonpsychotic
n = 32 n = 271 P
Female 19 (59.4%) 165 (60.9%) .869
Age 36.9 ± 13.4 39.8 ± 11.9 .210
Marital status .036
Single/never married 22 (68.8%) 121 (44.6%)
Married or living as married 6 (18.8%) 90 (33.2%)
Separated/widowed 4 (12.5%) 50 (22.1%)
Educational background .034
Less than high school 5 (15.6%) 12 (4.4%)
High school or GED 10 (31.2%) 56 (20.7%)
Some college 7 (21.9%) 75 (27.7%)
Tech school or associates degree 4 (12.5%) 37 (13.7%)
College diploma 3 (9.4%) 73 (26.9%)
Graduate or professional degree 3 (9.4%) 18 (6.6%)
Employed 6 (18.8%) 102 (37.6%) .035
Bipolar I disorder 25 (78.1%) 171 (63.1%) .093
Comorbid conditions
Panic disorder (current) 12 (37.5%) 63 (23.2%) .077
Agoraphobia (current) 18 (56.2%) 95 (34.9%) .017
Social phobia (current) 12 (37.5%) 66 (24.4%) .018
GAD (current) 13 (40.6%) 62 (22.9%) .028
OCD (current) 5 (15.6%) 26 (9.6%) .538
PTSD (current) 5 (15.6%) 31 (11.4%) .489
ADHD (current) 10 (31.2%) 61 (22.4%) .509
Any substance use disorder lifetime 19 (59.4%) 170 (62.7%) .711

Note: Statistics reported are n (%) for categorical variables and mean ± SD for continuous variables. P-values reported are based on 𝜒 2 test for categorical
variables and t test for continuous variables.
GED, general education development; BISS, Bipolar Inventory of Symptoms Scale; GAD, generalized anxiety disorder; OCD, obsessive–compulsive disorder;
PTSD, posttraumatic stress disorder; ADHD, attention-deficit hyperactivity disorder.

TA B L E 2 Severity at baseline and after 6 months of treatment. psychotic versus nonpsychotic depressive episodes

Baseline 6 Months
Psychotic Nonpsychotic Psychotic Nonpsychotic
n = 32 n = 271 P n = 28 n = 247 P
BISS overall 75.2 ± 17.6 54.9 ± 16.3 <.001 37.2 ± 19.7 26.3 ± 18.0 .003
BISS depression domain 29.5 ± 7.0 24.9 ± 8.0 .002 13.0 ± 8.6 10.9 ± 9.5 .253
CGI BP overall 5.1 ± .9 4.5 ± .8 <.001 3.4 ± 1.3 2.8 ± 1.3 .032
CGI BP depression 4.9 ± .9 4.4 ± .9 .006 3.1 ± 1.4 2.6 ± 1.3 .07

Note: Statistics reported are mean ± SD. P-values reported are based on t test.
BISS, Bipolar Inventory of Symptoms Scale; CGI BP, Clinical Global Impression Bipolar version.

age (37.7 vs. 35.3; P = .644), gender (57.1 vs. 63.3% of female gen-
der; P = .722), or proportion of BD-I (81.0 vs. 72.7%; P = .667)
between quetiapine- and lithium-based treatment groups. Depression-
specific severity as well as psychosis severity (assessed by the psy-
chosis domains of the BISS) also did not differ significantly between the
two treatment groups. Improvement was observed during study for all
outcomes (overall, depression, and psychotic severity), but there were
no differences between groups in the symptom severity scores at the
end of the study (see Table 3). Remission rates were 50% in the lithium
group and 54% in the quetiapine group (P = .923).
We also compared the two treatment groups in terms of overall,
depression-specific, and psychosis-specific change scores on the BISS
with mixed model regression (see Fig. 2 for overall BISS score). Similar
to previous analyses, we observed significant time effects (BISS total:
F = 57.0; P < .001—BISS depression: F = 50.5; P < .001—BISS psy-
chosis: F = 24.9; P < .001); however, there were no significant group
CALDIERARO ET AL .
F I G U R E 1 Change on total BISS score over study duration. Psy-
chotic versus nonpsychotic bipolar depression
Note: Bars represents 2 standard errors
differences (BISS total: F = .1; P = .739—BISS depression: F = .04;
P = .844—BISS psychosis: F = .9; P = .344) or interaction effects (BISS
total: F = .6; P = .428—BISS depression: F = .3; P = .603—BISS psy-
chosis: F = .4; P = .558). The same was observed for remission rates in
the Cox regression (hazard ratio = .937; P = .908). These results indi-
cated that significant improvement from baseline was observed over
time for the subgroup of psychotic depression as a whole, but there
were no significant differences in the rate of improvement or time to
remission between treatment groups.
Finally, the CGI-EI-BP was used to compare the effectiveness of the
two treatments in the participants presenting psychotic symptoms. In
the mixed model regression, there was only a significant main effect for
time (F = 15.2; P < .001), with no significant group (F = .7; P = .417) or
group × time interaction effects (F = .02; P = .897). Thus, the effective-
ness of lithium was similar to that of quetiapine over time, for patients
presenting psychotic depressive episode.
4 DISCUSSION
To the best of our knowledge, this is the first study comparing treat-
ment outcomes of currently psychotic and nonpsychotic bipolar
depressive episodes. We found that, despite presenting with more
severe depressive episodes at baseline, the treatment response of
participants with psychotic symptoms was similar to those without
psychosis. Furthermore, treatment response was similar not only in
magnitude, but also in course of change as measured by symptom
TA B L E 3 Severity at baseline and after 6 months of treatment in those with psychosis according to treatment group
Baseline
Quetiapine + APT (n = 21) Lithium + ATP (n = 11)
BISS overall 77.1 ± 19.1 71.5 ± 14.6
BISS depression domain 29.1 ± 7.5 30.2 ± 6.4
BISS psychosis domain 5 ± 2.4 4.8 ± 1.9
CGI BP overall 5.0 ± 1.0 5.4 ± .7
CGI BP depression 4.8 ± 1.0 5.2 ± .8
Note: Statistics reported are mean ± SD. P-values reported are based on t test.
BISS, Bipolar Inventory of Symptoms Scale; CGI BP, Clinical Global Impression Bipolar version.
5
F I G U R E 2 Change on total BISS score over study duration for bipo-
lar depression with psychosis, according to treatment group
Note: Bars represents 2 standard errors
improvement and cumulative remission across time points. This
pattern was not differentially affected by the use of a classical mood
stabilizer (lithium) or a second-generation antipsychotic (quetiapine).
The similar course of improvement in depressed patients with and
without psychotic symptoms is consistent with a previous study on
participants with BD in manic and mixed episodes, which found that
psychosis was not associated with a longer time to recovery (Tohen
et al., 2003b). Furthermore, a previous study of participants with bipo-
lar depression found no association between psychosis and time to
recovery; however, this study assessed lifetime, instead of current, psy-
chosis (Pallaskorpi et al., 2015). In contrast, Solomon et al. reported
a lower probability of recovery in BD-I patients presenting a mood
episode with severe onset, defined by the presence of psychosis or
severe psychosocial impairment (Solomon et al., 2010). Two large stud-
ies in unipolar depression contrast with our findings in bipolar individ-
uals by reporting a longer time to recover when psychosis was present
(Coryell et al., 1996; Maj, Pirozzi, Magliano, Fiorillo, & Bartoli, 2007),
consistent with potential differences in the prognostic impact of psy-
chosis on bipolar depression and MDD.
Interestingly, we observed no significant difference in treatment
outcome between psychotic participants receiving quetiapine and
those receiving lithium. This aligns with the main outcomes of the
CHOICE study, which showed similar effectiveness of lithium and
quetiapine for BD in general (Nierenberg et al., 2016). These data were
also consistent with a small open study of bipolar and unipolar patients,
which concluded the addition of an antipsychotic was not necessarily
indicated for all patients with psychotic depression (Grunze, Marcuse,
6 Months
p Quetiapine + APT (n = 18) Lithium + ATP (n = 10) P
.403 37.9 ± 22.0 35.8 ± 15.7 .788
.686 13.9 ± 9.5 11.3 ± 6.8 .446
.872 1.8 ± 2.4 1.2 ± 1.5 .503
.289 3.4 ± 1.3 3.2 ± 1.4 .645
.230 3.1 ± 1.4 3.2 ± 1.4 .788
6 CALDIERARO ET AL .
Schärer, Born, & Walden, 2002). However, the generalizability of our
results must be considered with caution, given that we assessed only
outpatients. Additionally, the smaller number of psychotic participants
limited the power of comparisons within this subgroup. In contrast
to these results, Ozyildirim et al. found that bipolar participants were
more likely to respond to lithium when psychosis was not present
(Ozyildirim et al., 2010). However, this study differed from the current
study in that included only BD-I patients, pooled results of all mood
episodes, and compared patients with psychosis in all episodes with
those who had never experienced psychosis rather than those who
were not currently experiencing it.
The Bipolar CHOICE study included only outpatients and most
depressed participants were in the moderate range of severity. The
overall remission rates were consistent with other pragmatic clinical
trials on outpatients with BD (Nierenberg et al., 2013; Sachs et al.,
2007). However, there are some discrepancies in the literature worth
noting. A large placebo-controlled randomized clinical trial (RCT) on
the olanzapine–fluoxetine combination for depression in BD-I included
more severe cases and both inpatients and outpatients (Tohen et al.,
2003a). The remission rates were higher than those observed in the
present study and the combined treatment was more effective than
the monotherapy with olanzapine. However, a direct comparison to our
results is limited because the criterion for remission was less restric-
tive, and although a significant proportion of participants presented
with psychosis, the impact of these features on the outcomes of the
study was not reported. Additionally, the RCT EMBOLDEN I com-
pared quetiapine versus lithium for bipolar depression (Young et al.,
2010). Although psychosis was not an exclusion criteria, the proportion
of patients presenting psychotic symptoms and the impact of these
symptoms on the treatment outcomes was not reported. The remis-
sion rates were higher than those in the Bipolar CHOICE study even
for the placebo group, and only quetiapine was more effective than
placebo. A less restrictive selection of participants and a more restric-
tive criterion for remission in the Bipolar CHOICE study are possible
explanations for these discrepancies. In light of this, our results are
of particular importance for the ability to analyze the presence and
treatment-specific response of bipolar depression with psychosis in
a representative outpatient setting. However, our results cannot be
extrapolated to the full range of severity of bipolar depression or to
inpatient populations; it is possible that patients with more severe psy-
chotic episodes that require hospitalization would have more marked
differences in treatment outcome when compared to patients with
depressive episodes without psychosis.
Our results must be considered within the context of their lim-
itations. First, despite the large study population, the group with
psychotic features is small, resulting in a limited statistical power,
particularly for the comparisons within this group. The overlap in the
symptom improvement curves of those receiving lithium and those
receiving quetiapine (Fig. 2) suggests that the response to both these
treatments was not different among participants with psychosis.
However, a lack of statistical power cannot be excluded as the reason
for negative results. Therefore, the findings of this study should be
considered exploratory and require replication with larger samples.
Second, this is a secondary analysis of a trial where randomization was
not based on the presence of psychotic features. Third, the sample
was composed only of outpatients, which may have resulted in a more
mildly impaired subset of psychotic depression, as well as a relatively
small number of psychotic patients in general. Fourth, psychosis was
not a primary outcome measure for the Bipolar CHOICE study, and,
therefore, the presence of psychosis was assessed only through items
of the BISS. Finally, quetiapine was the only antipsychotic evaluated,
and the combination of quetiapine plus lithium was not tested.
5 CONCLUSION
Our findings indicate that despite greater severity at baseline, bipo-
lar depressive episodes with versus without psychotic features did not
have significantly different treatment responses. No significant dif-
ferences between lithium and quetiapine were observed, suggesting
that a mood stabilizer may be effective for treating bipolar depression
with psychosis in outpatients. However, because the limited statistical
power due to the small number of participants with current psychotic
features, these findings need replication in a larger sample. Future
studies in bipolar depressive episodes with psychosis should evaluate
the effect of other antipsychotics as well as the combination of antipsy-
chotics with mood stabilizers in the treatment of these patients.
ACKNOWLEDGMENTS
The Bipolar CHOICE study was funded by the Agency for Health-
care Research and Quality (AHRQ), 1R01HS019371-01. Part of this
work has been supported by the Dauten Family Center for Bipo-
lar Treatment Innovation. Marco Antonio Caldieraro was supported
by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES), program 227—Pesquisa Pós-doutoral no Exterior (grant
88881.120434/2016-01).
CONFLICT OF INTEREST
Dr. Marco Antonio Caldieraro reports no competing interests.
Dr. Louisa G. Sylvia was a shareholder in Concordant Rater Systems
and serves as a consultant for United Biosource Corporation and Clin-
tara. She receives royalties from New Harbinger. Mr. Steven Dufour
reports no competing interests.
Ms. Samantha Walsh reports no competing interests. Ms. Jessica
Janos reports no competing interests. Dr. William V. Bobo has received
research support from NIMH, AHRQ, and the Mayo Foundation for
Medical Education and Research. Dr. Keming Gao have been on a
speakers bureau and an advisory board of Sunovion, and received
grant supports from AstraZeneca, Brain and Behavior Research Foun-
dation, and Cleveland Foundation. Dr. Mauricio Tohen is a former
full-time employee at Lilly (1997–2008). He has been a consultant
for AstraZeneca, Abbott, BMS, Lilly, GSK, J&J, Otsuka, Roche, Lund-
beck, Elan, Alkermes, Merck, Pamlab, Alexza, Forest, Teva, Sunovion,
Gedeon Richter, and Wyeth. His spouse is a former employee at
Lilly (1998–2013). Dr. Noreen A. Reilly-Harrington receives royalties
from Oxford University Press, the American Psychological Association,
CALDIERARO ET AL .
and New Harbinger. She serves as a consultant for United Biosource
Corporation and was a shareholder in Concordant Rater Systems. Dr.
Terence A. Ketter has the following financial interests/arrangements
or affiliations that could be perceived as real or apparent conflicts of
interest: Grant/research support from the AstraZeneca Pharmaceuti-
cals LP, Cephalon Inc., Eli Lilly and Company, Pfizer Inc., and Sunovion
Pharmaceuticals; Consultant Fees from Allergan, Inc., Avanir Pharma-
ceuticals, Bristol-Myers Squibb Company, Cephalon Inc., Forest Phar-
maceuticals, Janssen Pharmaceutica Products, LP, Merck & Co., Inc.,
Sunovion Pharmaceuticals, Teva Pharmaceuticals; Lecture Honoraria
from Abbott Laboratories, Inc., AstraZeneca Pharmaceuticals LP, Glax-
oSmithKline, and Otsuka Pharmaceuticals; and Publication Royalties
from American Psychiatric Publishing, Inc. In addition, Dr. Ketter's
spouse is an employee of and holds stock in Janssen Pharmaceuti-
cals. Dr. Susan L. McElroy is a consultant to or member of the scien-
tific advisory boards of Allergen, Alkermes, Corcept, Ironshore, MedA-
vante, Naurex, NovoNordisk, Shire, Sunovian, and Teva. She is a princi-
pal or co-investigator on studies sponsored by the Agency for Health-
care Research & Quality (AHRQ), Azevan, Alkermes, AstraZeneca,
Cephalon, Eli Lilly and Company, Marriott Foundation, National Insti-
tute of Mental Health, Orexigen Therapeutics, Inc., Shire, Sunovian,
Takeda Pharmaceutical Company Ltd., and Transcept Pharmaceutical,
Inc. She is also an inventor on U.S. Patent No. 6,323,236 B2, Use of
Sulfamate Derivatives for Treating Impulse Control Disorders, and
along with the patient's assignee, University of Cincinnati, Cincinnati,
Ohio, has received payments from Johnson & Johnson, which has
exclusive rights under the patent. Dr. Richard C. Shelton has received
grant funding from Alkermes, Inc.; Assurex Health; Avanir Pharma-
ceuticals; Cerecor, Inc.; Janssen Pharmaceutica; Novartis, Inc.; Otsuka
Pharmaceuticals; Nestle’ Health, and Takeda Pharmaceuticals. He has
been a consultant for Allergan; Cerecor, Inc.; Clintara LLC; Janssen
Pharmaceutica; Medtronic, Inc.; MSI Methylation Sciences, Inc.; Nes-
tle’ Health; Pfizer, Inc.; and Takeda Pharmaceuticals. Dr. Charles L.
Bowden has no competing interests. Dr. Thilo Deckersbach research
has been funded by NIH, NIMH, NARSAD, TSA, IOCDF, Tufts Univer-
sity, DBDAT, Otsuka Pharmaceuticals, and Cogito, Inc. He has received
honoraria, consultation fees, and/or royalties from the MGH Psychi-
atry Academy, BrainCells Inc., Clintara, LLC., Systems Research and
Applications Corporation, Boston University, the Catalan Agency for
Health Technology Assessment and Research, the National Associ-
ation of Social Workers Massachusetts, the Massachusetts Medical
Society, Tufts University, NIDA, NIMH, and Oxford University Press.
He has also participated in research funded by DARPA, NIH, NIMH,
NIA, AHRQ, PCORI, Janssen Pharmaceuticals, The Forest Research
Institute, Shire Development Inc., Medtronic, Cyberonics, Northstar,
Takeda, and Sunovion. Dr. Andrew A. Nierenberg is a consultant
for Abbott Laboratories, Alkermes, American Psychiatric Association,
Appliance Computing Inc. (Mindsite), Basliea, Brain Cells, Inc., Brandeis
University, Bristol Myers Squibb, Clintara, Corcept, Dey Pharmaceuti-
cals, Dainippon Sumitomo (now Sunovion), Eli Lilly and Company, EpiQ,
L.P./Mylan Inc., Forest, Genaissance, Genentech, GlaxoSmithKline,
Healthcare Global Village, Hoffman LaRoche, Infomedic, Intra-Cellular
Therapies, Lundbeck, Janssen Pharmaceutica, Jazz Pharmaceuticals,
Medavante, Merck, Methylation Sciences, NeuroRx, Naurex, Novartis,
7
PamLabs, Parexel, Pfizer, PGx Health, Otsuka, Ridge Diagnostics Shire,
Schering-Plough, Somerset, Sunovion, Takeda Pharmaceuticals, Targa-
cept, and Teva; consulted through the MGH Clinical Trials Network
and Institute (CTNI) for Astra Zeneca, Brain Cells, Inc, Dianippon Sum-
itomo/Sepracor, Johnson and Johnson, Labopharm, Merck, Methyla-
tion Science, Novartis, PGx Health, Shire, Schering-Plough, Targacept,
and Takeda/Lundbeck Pharmaceuticals. He is a stakeholder in Appli-
ance Computing, Inc. (MindSite), Brain Cells, Inc., and Medavante.
He receives research support from American Foundation for Suicide
Prevention, AHRQ, Brain and Behavior Research Foundation, Bristol-
Myers Squibb, Cederroth, Cephalon, Cyberonics, Elan, Eli Lilly, For-
est, GlaxoSmithKline, Intra-Cellular Therapies, Janssen Pharmaceu-
tica, Lichtwer Pharma, Marriott Foundation, Mylan, NIMH, PamLabs,
PCORI, Pfizer Pharmaceuticals, Shire, Stanley Foundation, Takeda,
and Wyeth-Ayerst. Honoraria include Belvoir Publishing, University of
Texas Southwestern Dallas, Brandeis University, Bristol-Myers Squibb,
Hillside Hospital, American Drug Utilization Review, American Society
for Clinical Psychopharmacology, Baystate Medical Center, Columbia
University, CRICO, Dartmouth Medical School, Health New England,
Harold Grinspoon Charitable Foundation, IMEDEX, International Soci-
ety for Bipolar Disorder, Israel Society for Biological Psychiatry, Johns
Hopkins University, MJ Consulting, New York State, Medscape, MBL
Publishing, MGH Psychiatry Academy, National Association of Contin-
uing Education, Physicians Postgraduate Press, SUNY Buffalo, Univer-
sity of Wisconsin, University of Pisa, University of Michigan, University
of Miami, University of Wisconsin at Madison, APSARD, ISBD, SciMed,
Slack Publishing and Wolters Kluwer Publishing, ASCP, NCDEU, Rush
Medical College, Yale University School of Medicine, NNDC, Nova
Southeastern University, NAMI, Institute of Medicine, CME Institute,
ISCTM, World Congress on Brain Behavior and Emotion, Congress of
the Hellenic Society for Basic and Clinical Pharmacology, and ADAA.
He has copyright joint ownership with MGH for Structured Clinical
Interview for MADRS and Clinical Positive Affect Scale.
ORCID
Marco Antonio Caldieraro MD, PhD
http://orcid.org/0000-0002-4355-9547
Samantha Walsh BS http://orcid.org/0000-0001-7343-0405
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How to cite this article: Caldieraro MA, Dufour S, Sylvia LG,
et al. Treatment outcomes of acute bipolar depressive episode
with psychosis. Depress Anxiety. 2018;1–9. https://doi.org/
10.1002/da.22716