International Journal of Neuropsychopharmacology (2009), 12, 773–782.

Copyright f 2008 CINP ARTICLE

doi:10.1017/S1461145708009735

Olanzapine/fluoxetine combination vs.

CINP
lamotrigine in the 6-month treatment of
bipolar I depression

Eileen Brown1, David L. Dunner2, Susan L. McElroy3, Paul E. Keck Jr.3,4,

David H. Adams1, Elisabeth Degenhardt1, Mauricio Tohen1,5 and John P. Houston1
1
Lilly Research Laboratories, Indianapolis, IN, USA
2
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
3
Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati,
OH, USA

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4
Mental Health Service Line and General Clinical Research Center, Cincinnati Veterans Affairs Medical Center, Cincinnati,
OH, USA
5
McLean Hospital, Harvard Medical School, Belmont, MA, USA

Abstract
To determine the efficacy and tolerability of olanzapine/fluoxetine combination (OFC) compared with
lamotrigine (Lam) for long-term treatment of bipolar I depression, this 25-wk, randomized, double-blind
study compared OFC (6/25, 6/50, 12/25, or 12/50 mg/d, n=205) with Lam titrated to 200 mg/d (n=205)
in patients with bipolar I disorder, depressed. A protocol-specified analysis of 7-wk outcomes was pre-
viously reported. Outcome measures included Clinical Global Impressions – Severity of Illness (CGI-S)
(primary), Montgomery–Asberg Depression Rating Scale (MADRS), and Young Mania Rating Scale
(YMRS) scores. OFC-treated patients had significantly greater improvement than Lam-treated patients
over 25 wk on CGI-S (p=0.008), MADRS (p=0.005), and YMRS (p<0.001) scores, and from baseline across
visits from week 5 (titration complete) to the end of the study on CGI-S (p=0.043), MADRS (p=0.017), and
YMRS (p=0.001) scores. Of patients in remission after the 7-wk acute phase, there was no significant
difference between treatment groups in the incidence of relapse (MADRS >15, p=0.528). Rate of treatment-
emergent mania was not significantly different by treatment (p=0.401). OFC-treated patients had
more frequent (p<0.05) somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor ;
Lam-treated patients had more frequent insomnia. There was a significant difference in incidence of
treatment-emergent cholesterol o240 (p<0.001) and in weight gain of o7 % (p<0.001) in favour of the
Lam group. Patients with bipolar I depression had significantly greater symptom improvement over
25 wk on OFC compared with Lam. There was no treatment difference in incidence of relapse. OFC-
treated patients had more treatment-emergent adverse events and greater incidence of weight gain and
hypercholesterolaemia.
Received 30 June 2008 ; Reviewed 28 July 2008 ; Revised 31 October 2008 ; Accepted 11 November 2008 ;
First published online 11 December 2008
Key words : Antipsychotic, bipolar depression, clinical trial, mania, response.

Introduction acute and long-term pharmacological treatment of

Depressive symptoms and episodes are a substantial
source of morbidity and disability in the course of
bipolar disorder (Judd et al. 2005 ; Post et al. 2003). The
Address for correspondence : E. Brown, Ph.D., Eli Lilly and Company,
Lilly Corporate Center, Drop Code 6046, Indianapolis, IN 46285, USA.
Tel. : (317) 655-1568 Fax : (303) 258-9532
Email : ebrown@lilly.com
bipolar depression represents a substantial clinical
challenge, being an understudied area (Keck et al. 2003).
Indeed, there are no medications approved by the US
FDA for long-term treatment of bipolar depression.
The only treatments approved by the FDA for bipolar I
depression, i.e. olanzapine/fluoxetine combination
(OFC) and quetiapine, are presently only approved for
short-term use. In a large, double-blind, 8-wk, placebo-
controlled study in patients with bipolar depression,
774 E. Brown et al.
patients treated with OFC showed statistically signifi-
cant improvement in depressive symptoms compared
with the placebo group, from week 1 to week 8 (Tohen
et al. 2003). The safety profile of OFC appeared similar
to that of olanzapine (Olz) and fluoxetine (Flu) (Corya
et al. 2003 ; Tohen et al. 2003), and there was no increase
in treatment-emergent mania with OFC (Keck et al.
2005).
Lamotrigine (Lam) is a first-line treatment rec-
ommendation for bipolar depression according to sev-
eral bipolar treatment guidelines, including the 2002
American Psychiatric Association practice guidelines
(APA, 2002 ; Suppes et al. 2005 ; Yatham et al. 2005).
Lam is FDA approved for maintenance treatment of
bipolar disorder. Two randomized, placebo-controlled
maintenance studies demonstrate the efficacy of Lam
in preventing depressive relapse, one in patients with
an index episode of mania or hypomania (Bowden et al.
2003) and the other in patients with an index episode
of depression (Calabrese et al. 2003). In addition, two
studies suggest that Lam may be effective for acute
treatment of bipolar depression (Calabrese et al. 1999 ;
Frye et al. 2000). In a 7-wk, double-blind, placebo-
controlled trial in patients with bipolar I depression,
Lam had greater efficacy than placebo at doses of
50 or 200 mg/d (Calabrese et al. 1999). A more recent
analysis of five placebo-controlled studies of Lam in
bipolar I and II depression including the positive
study above and four additional studies that had
not been previously fully disclosed in peer-reviewed
publications, indicated that Lam did not separate
from placebo on the primary outcome measure in
the additional studies (Calabrese et al. 2008). A slow
titration from an initial dosage of 25 mg/d up to
200 mg/d over several weeks is recommended to re-
duce the incidence of serious rash (Calabrese et al.
2002).
Given the existing clinical data on OFC and Lam, a
direct comparison of these treatments in the ‘long-
term ’ treatment of bipolar I depression is of sub-
stantial clinical relevance. The first reported direct
comparison of OFC and Lam for acute bipolar I
depression demonstrated statistically greater improve-
ment in depressive and manic symptoms in OFC-
treated patients, along with a higher incidence of
adverse events in the OFC-treated patients over 7 wk
treatment (Brown et al. 2006). The slow titration of
Lam over 5 wk may have limited efficacy in this short
time-period. Here we report the results of the entire
25-wk study including the previously reported first
7 wk. To our knowledge, this is the first controlled
study of two medications in the long-term treatment of
bipolar I depression.
Materials and methods
Patient population
This study was conducted in patients aged 18–60 yr
who were outpatients or hospital in-patients. The
study protocol was approved by the sites’ institutional
review boards, and written informed consent was
obtained from all participants prior to study entry.
Patients met DSM-IV criteria for bipolar I disorder,
depressed, based on the Structured Clinical Interview
for DSM-IV (SCID). Patients who met DSM-IV criteria
for a mixed state were excluded. Inclusion criteria re-
quired a total score o20 on the Montgomery–Asberg
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Depression Rating Scale (MADRS ; Montgomery &
Asberg, 1979) and a rating o4 (moderately ill) on
the Clinical Global Impressions – Severity of Illness
(CGI-S) scale (Guy, 1976). Patients must also have ex-
perienced at least one lifetime previous manic or
mixed episode of sufficient severity to require treat-
ment with a mood stabilizer or antipsychotic. Ex-
clusion criteria included serious suicidal risk, DSM-IV
substance dependence within the previous 30 d (ex-
cept nicotine and caffeine), a Young Mania Rating
Scale (YMRS ; Young et al. 1978) total score o15 at
randomization, and current diagnosis of any of the
following according to DSM-IV-TR criteria : schizo-
phrenia, schizophreniform disorder, schizoaffective
disorder, delusional disorder, delirium of any type,
dementia of any type, amnestic disorder, any sub-
stance-induced disorder, or any psychotic disorder
due to a general medical condition. Patients who were
currently taking or had previously failed or responded
poorly to an adequate trial of either Olz, Olz+an anti-
depressant, or Lam were also excluded. The study was
conducted between November 2003 and January 2005
at 38 sites throughout the USA.
Study design
This was a randomized, double-blind, parallel group
study. Psychotropic agents were tapered off gradually
and discontinued by 24 h prior to randomization. For
patients tapering off lithium or Flu, a taper period of
up to 5 wk was allowed. The results of the first 7 wk of
the trial (acute phase) have previously been reported
(Brown et al. 2006). The present study reports results of
the entire 25 wk including the first 7 wk. As specified
in the study protocol, efficacy and safety outcomes
were analysed from baseline across the entire 25 wk.
Major efficacy outcome data were also analysed as
change from baseline from the end of the Lam titration
period (week 5) to the end of the 25-wk study.
Patients randomized to Lam received 25 mg on the
day of randomization and were titrated up to 200 mg
 Olanzapine+fluoxetine vs. lamotrigine in bipolar depression
over 5 wk per package insert recommendation. After
the titration period, the Lam dose could be decreased
to 150 mg/d if patients could not tolerate the target
dose. Patients randomized to OFC started on 6 mg Olz
and 25 mg Flu (6/25), and were increased to 12 mg Olz
and 25 mg Flu (12/25) after 1 wk. After 1 d on 12/25,
dosage could be adjusted to any of four possible
doses : 6/25, 12/25, 6/50, or 12/50. To preserve the
blind nature of the study, the number of capsules and
treatment frequency were identical for each group.
Anticholinergic medication was permitted for extra-
pyramidal symptoms (benztropine mesylate ; 6 mg/d
maximum, but not for prophylaxis), and benzodiaze-
pines/hypnotics were permitted if needed (up to
2 mg/d of lorazepam equivalents).
Outcome measures
The primary outcome measure and analysis, as de-
fined in the protocol, was the change in CGI-S from
baseline across the 7-wk acute portion of the study
(Brown et al. 2006). For the present 25-wk analysis,
the CGI-S was the primary outcome measure. The
MADRS was used to assess improvement in depress-
ive symptoms and the YMRS to evaluate any change
in manic symptoms. Other outcome measures in-
cluded the Brief Symptom Inventory (BSI ; Derogatis &
Spencer, 1982), the Global Assessment of Functioning
(GAF) scale, the Brief Psychiatric Rating Scale (BPRS),
Clinical Global Impressions – Improvement of Illness
(CGI-I), and Patient Global Impression – Improvement
(PGI-I). CGI-I and PGI-I measure improvement from 1
(very much better) to 7 (very much worse) and were,
therefore, not used at baseline but were used every
visit starting with week 1.
Safety was assessed by the evaluation of treatment-
emergent adverse events, discontinuations due to ad-
verse events, vital sign measurements, and clinical
laboratory tests. Clinical laboratory tests were per-
formed by a central laboratory, Covance Inc. (USA),
and Covance reference ranges were used to determine
abnormal laboratory values except for total choles-
terol, HDL cholesterol, LDL cholesterol, triglycerides,
and fasting glucose, for which the National Chol-
esterol Education Program (NCEP) guidelines were
used (Expert Panel, 2001).
Statistical methods
A mixed-model repeated-measures (MMRM) ap-
proach was used to analyse key efficacy variables with
visit, treatment, investigator, visitrtreatment interac-
tion, and baseline score in the model. An unstructured
covariance matrix was fit to within-patient repeated
775
measures. To assess the differential treatment effects
across the entire 25-wk, double-blind treatment per-
iod, the main effect of treatment from the MMRM
model was defined as the primary analysis method.
As a secondary, post-hoc analysis, overall change from
baseline across visits from week 5 (titration complete)
to the end of the study was compared between treat-
ment groups using appropriate contrast within the
MMRM model. In addition, change from baseline
to each visit was tested between treatment groups
within the repeated-measures model. In addition to
the primary methodology, an analysis of variance
(ANOVA) was performed for the key efficacy vari-
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ables and the BSI on the change from baseline to end-
point, last observation carried forward (LOCF). The
model included treatment, investigator, and baseline
score.
Response was defined in two different ways : o50 %
reduction in MADRS total score ; or a CGI-S score f3
(mildly ill). Remission was defined as an endpoint
(last observation available) MADRS total score f12.
Rate of response was compared between groups with
Fisher’s exact test, and time to event (response or re-
mission) was compared between groups using a log-
rank test. Relapse was defined as the proportion of
patients reaching a MADRS total score o15 at any
time after week 7 after being in remission at the end of
the 7-wk acute phase.
Treatment-emergent adverse events and rates of
discontinuation were compared between treatment
groups with Fisher’s exact test. A descriptive post-
hoc analysis was done to evaluate the timing of the
most common treatment-emergent adverse events by
calculating the proportion of the event that started
within the first 3 wk out of the total number of events.
Change from baseline to endpoint (LOCF) in lab-
oratory values and vital signs were compared be-
tween treatment groups with ANOVA, with treatment,
investigator, and baseline value in the model.
Treatment-emergent abnormal laboratory values were
compared between treatment groups using Fisher’s
exact test.
All analyses were based on the intent-to-treat prin-
ciple and were performed using Statistical Application
Software (SAS1 ; SAS Institute, USA). All tests of
treatment effects were conducted at a two-sided a-
level of 0.05. Investigators with fewer than two ran-
domized patients per treatment group were pooled for
statistical analysis purposes. The study was designed
to detect a difference between treatment groups in the
change from baseline in CGI-S (overall treatment effect
from MMRM model in the 7-wk acute phase) of 0.29
with 90 % power.
776 E. Brown et al.

Table 1. Patient characteristics and illness severity at baseline

OFC (n=205) Lam (n=205) Total (n=410)

Female ( %) 57.6 62.4 60.0

Caucasian ( %) 80.5 82.9 81.7
Age, mean yr (S.D.) 36.8 (11.5) 37.2 (10.7) 37.0 (11.1)
Psychotic features ( % yes) 4.4 7.3 5.9
Age of onset, mean yr (S.D.) 18.7 (8.0) 19.3 (8.1) 19.0 (8.0)
Rapid cycling ( % yes) 33.2 35.1 34.1
Outpatients ( %) 99.0 99.5 99.3
CGI-S, mean (S.D.)a 4.63 (0.66) 4.63 (0.63) 4.63 (0.64)
MADRS total score, mean (S.D.)a 30.94 (5.42) 31.35 (5.23) 31.15 (5.33)
YMRS total score, mean (S.D.)a 5.21 (3.51) 4.64 (3.26) 4.92 (3.39)

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GAF total score, mean (S.D.)a 52.18 (6.33) 52.83 (6.08) 52.50 (6.21)
BPRS total score, mean (S.D.)a 21.79 (9.74) 22.22 (9.67) 22.00 (9.69)

OFC, Olanzapine/fluoxetine combination ; Lam, lamotrigine ; S.D., standard deviation ; CGI-S, Clinical Global
Impressions – Severity of Illness ; MADRS, Montgomery–Asberg Depression Rating Scale ; YMRS, Young Mania Rating Scale ;
GAF, Global Assessment of Functioning ; BPRS, Brief Psychiatric Rating Scale.
a
For those patients with baseline and at least 1 post-baseline measurement : n=202 OFC ; n=191 Lam.

Results 6/25, and 13.7 % at 6/50 mg/d ; 73.8 % of the Lam

Patient and illness characteristics
The study included 410 randomized patients (OFC,
n=205 ; Lam, n=205). At baseline, patient character-
istics and illness severity in the treatment groups were
comparable (Table 1). Participants were mostly out-
patients and predominately Caucasian. In general,
patients were moderately to severely depressed with
minimal manic symptoms.
Treatment disposition
The proportion of patients completing the 25-wk,
double-blind period was similar for both treatment
groups (OFC 33.2 % vs. Lam 33.7 %, p=1.00). Of the
137 OFC-treated patients and 134 Lam-treated patients
who completed the study’s 7-wk acute portion, 49.6 %
and 51.5 % completed the entire 25 wk, respectively.
The most common reasons for discontinuation across
the 25 wk were ‘lost to follow-up’ (OFC 16.1 % vs. Lam
24.9 %), patient decision (OFC 18.0 % vs. Lam 13.2 %),
and adverse events (OFC 18.0 % vs. Lam 13.2 %). Rash
(OFC 1.5 % vs. Lam 3.9 %) and weight increase (OFC
2.9 % vs. Lam 0.0 %) were the most common adverse
events leading to discontinuation. Lack of efficacy was
a less frequent reason for discontinuation (OFC 4.9 %
vs. Lam 5.4 %). One patient in the Lam group died
during the study due to a car accident.
Study drug dose
The frequency of the final daily doses for OFC were
54.6 % patients at 12/50, 17.7 % at 12/25, 13.7 % at
patients reached the optimal dose of 200 mg/d. Of
those reaching 200 mg/d, 6.1 % subsequently reduced
their dose to 150 mg/d. The remaining patients dis-
continued the study prior to completing the titration
algorithm. The mean modal daily dose for OFC-
treated patients was 40.8 mg Flu and 10.7 mg Olz, and
for Lam-treated patients it was 149.7 mg, including
those patients who discontinued early.
Efficacy
The OFC group had significantly greater improvement
on average across the 25 wk on CGI-S compared to the
Lam group (p=0.008 overall MMRM, overall effect
size=0.22, Fig. 1 a). The OFC group had significantly
greater improvement at weeks 1, 2, 4, 5, 6, and 17 (p<
0.05). Analysing the mean (S.E.) change from baseline
across visits from week 5 (titration complete) to the
end of the study, the OFC group had significantly
greater improvement [OFC x2.06 (0.08), Lam x1.83
(0.08), p=0.043]. Further, the LOCF analysis showed a
significant improvement for the OFC group compared
to the Lam group (OFC x1.84, Lam x1.57, p=0.038).
Using MADRS total score, greater improvements
in depressive symptoms were observed in the OFC
group compared to the Lam group (p=0.005 overall
MMRM, overall effect size=0.23, Fig. 1b) across the
25-wk study. The OFC group had significantly greater
improvement at weeks 1, 2, 4, 5, 6, 7, 17, and 25 (p<
0.05). Analysing the mean (S.E.) change from baseline
across visits from week 5 (titration complete) to the end
of the study, OFC-treated patients had significantly
 Olanzapine+fluoxetine vs. lamotrigine in bipolar depression 777

(a) greater improvement [OFC x19.26 (0.62), Lam x17.24

Weeks from randomization
0 2 4 6 8 10 12 14 16 18 20 22 24 26
(0.63), p=0.017]. The LOCF analysis also showed a
Change from baseline in

0 significant improvement for the OFC group compared

–0.5 Acute phase
to the Lam group (OFC x17.85, Lam x15.73, p=0.029
–1.0 LOCF). Individual MADRS items that showed stat-
CGI-S

*
–1.5 istically greater overall improvement for OFC-treated
*
* patients compared with Lam-treated patients (p<0.05
–2.0 *
* overall MMRM) were item 1, apparent sadness ; item 2,
–2.5 *
reported sadness ; item 3, inner tension ; item 4, reduced
Lam (n) 185 167 144 130 117 103 86 74
OFC (n) 196 181 154 132 117 101 83 73 sleep ; item 5, reduced appetite ; item 9, pessimistic
thoughts ; and item 10, suicidal thoughts. Lam was not
(b) 0 2 4 6 8 10 12 14 16 18 20 22 24 26
0 significantly better than OFC for any individual
MADRS item.
Change from baseline

Acute phase

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–5
Baseline manic symptoms were low for both groups
in MADRS

–10 as measured by YMRS total score (OFC 5.21 vs. Lam

* 4.64). However, greater improvements in manic symp-
–15
* toms were observed on average over the 25 wk in the
*
–20 * OFC group compared to the Lam group (p<0.001 over-
**
* * all MMRM, overall effect size=0.27, Fig. 1 c). Ana-
–25
Lam (n) 185 167 143 130 117 102 86 74 lysing the mean (S.E.) change from baseline across
OFC (n) 196 181 154 132 117 101 83 73 visits from week 5 (titration complete) to the end of the
(c) study, OFC-treated patients had significantly greater
0 2 4 6 8 10 12 14 16 18 20 22 24 26
0 improvement [OFC x2.28 (0.20), Lam x1.33 (0.20),
Change from baseline

Acute phase
p=0.001]. The LOCF analysis also showed a signifi-
–1 cant improvement for the OFC group compared to
in YMRS

** the Lam group (OFC x1.56, Lam x0.69, p=0.008

* LOCF).
–2
*
–3 * *
Lam (n) 185 167 142
OFC (n) 196 181 154
Fig. 1. Change to each scheduled visit in illness severity,
depressive, and manic symptoms across 25 wk treatment.
(a) Clinical Global Impressions – Severity of Illness (CGI-S)
total score. The olanzapine/fluoxetine combination
(OFC ; ) group had significantly greater improvement on
average compared to the lamotrigine (Lam ; ) group across
the 25 wk [least-squares mean (S.E.) : OFC x1.70 (0.07),
Lam x1.46 (0.07), p=0.008 overall mixed-model repeated
measures (MMRM)]. The OFC group had significantly
greater improvement at weeks 1, 2, 4, 5, 6, and 17 (* p<0.05).
(b) Montgomery–Asberg Depression Rating Scale (MADRS)
total score. The OFC group had significantly greater
improvement on average compared to the Lam group across
the 25 wk [least-squares mean (S.E.) : OFC x16.63 (0.52), Lam
x14.70 (0.52), p=0.005 overall MMRM]. The OFC group had
significantly greater improvement at weeks 1, 2, 4, 5, 6, 7, 17,
and 25 (* p<0.05). (c) Young Mania Rating Scale (YMRS) total
score. The OFC group had significantly greater improvement
on average compared to the Lam group across the 25 wk
[least-squares mean (S.E.) : OFC x1.92 (0.17), Lam x1.05
(0.17), p<0.001 overall MMRM]. The OFC group had
significantly greater improvement at day 3 and weeks 1, 2, 5,
7, 13, 17, and 25 (* p<0.05).
*
*
Response, remission, and relapse
130 117 103 86 74
132 117 101 83 73 Response rates did not significantly differ by treat-
ment group when response was defined as a o50 %
reduction in MADRS total score (OFC 64.4 % vs. Lam
55.0 %, p=0.064). However, the OFC group displayed
a significantly higher rate of response compared to the
Lam group when response was alternatively defined
as CGI-S f3 (mildly ill), a less widely used definition
(OFC 68.8 % vs. Lam 58.1 %, p=0.036). The time to 50 %
reduction in MADRS total score was significantly
shorter for the OFC group compared to the Lam group
[median days for OFC 21 (95 % CI 15–28) vs. 33 (95 %
CI 22–63) for Lam, p=0.013]. The rate of remission
(MADRS f12) was not significantly different between
groups (OFC 55.9 % vs. Lam 48.2 %, p=0.131), and the
time to remission did not significantly differ (median
days for OFC 35 vs. Lam 45, p=0.062).
Of patients in remission (MADRS f12) at the end of
the 7-wk acute phase (OFC 56.4 % vs. Lam 49.2 %,
p=0.158), the rate of relapse (MADRS >15) was not
significantly different between treatments (OFC 13/
95=13.7 % vs. Lam 14/77=18.2 %, p=0.528).
There were no significant differential effects on
improvement in efficacy measures (CGI-S, MADRS,
778 E. Brown et al.

Table 2. Brief Symptom Inventory (BSI)

Change from baseline to

Baseline, mean (S.D.) endpoint (LOCF), mean (S.D.)

OFC Lam OFC Lam p value

Global BSI Severity Index 1.70 (0.70) 1.65 (0.70) x0.79 (0.73) x0.58 (0.77) 0.006
Anxiety 1.73 (0.90) 1.64 (0.88) x0.82 (0.87) x0.58 (0.92) 0.020
Depression 2.17 (0.83) 2.17 (0.87) x1.07 (1.07) x0.90 (1.10) 0.080
Hostility 1.60 (1.08) 1.59 (0.96) x0.88 (1.01) x0.50 (1.09) <0.001
Interpersonal sensitivity 1.96 (1.04) 2.01 (1.06) x0.98 (1.05) x0.79 (1.07) 0.017
Obsessive compulsive 2.35 (0.88) 2.24 (0.91) x0.97 (1.00) x0.68 (1.09) 0.026
Paranoid 1.56 (1.02) 1.62 (1.00) x0.78 (0.88) x0.53 (0.96) <0.001

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Phobic 1.16 (1.05) 1.05 (1.00) x0.46 (0.77) x0.37 (0.85) 0.513
Psychoticism 1.65 (0.82) 1.59 (0.86) x0.73 (0.87) x0.61 (0.89) 0.193
Somatization 1.08 (0.77) 0.99 (0.77) x0.45 (0.78) x0.27 (0.69) 0.070

S.D.,
Standard deviation ; LOCF, last observation carried forward ; OFC, olanzapine/fluoxetine combination ; Lam, lamotrigine.
The BSI is a patient self-rated scale that is made up of 53 items and includes a global severity score along with nine different
scored dimensions. Average of items is taken to obtain each score which ranges from 0–4.

YMRS) with regard to patients’ gender, age, concomi-
tant benzodiazepine use, previous lithium use, rapid
cycling, or history of mixed episodes.
Treatment-emergent mania
The incidence of treatment-emergent mania was low,
and not significantly different between groups [OFC
5.0 % (10/202), Lam 7.3 % (14/191), p=0.401]. Of the 10
OFC-treated patients who relapsed into mania, 40 %
experienced treatment-emergent mania within the
first 3 wk, 40 % between weeks 4 and 7, and 20 % after
week 7 ; 60 % were rapid cyclers. Of the 14 Lam-treated
patients who relapsed into mania, 50 % experienced
treatment-emergent mania within the first 3 wk, 21 %
between weeks 4 and 7, and 29 % after week 7 ; 50 %
were rapid cyclers.
Additional efficacy outcomes
OFC-treated patients had significantly greater im-
provements compared to Lam-treated patients on the
GAF total score [overall change from baseline least-
squares mean (S.E.) : OFC 13.15 (0.61), Lam 11.50 (0.62),
p=0.046] as well as CGI-I [OFC 2.27 (0.06), Lam 2.48
(0.06), p=0.004] and PGI-I [OFC 2.47 (0.06), Lam 2.69
(0.06), p=0.007]. There were no significant differences
between groups in the BPRS total score [OFC x12.58
(0.54), Lam x11.69 (0.55), p=0.207]. OFC-treated
patients had a significantly greater improvement at
endpoint for the BSI – Global Severity Score (Table 2).
Safety and tolerability
Treatment-emergent adverse events with an incidence
>5 % for either treatment group are reported in
Table 3. Significantly more patients treated with OFC
reported somnolence, increased appetite, dry mouth,
sedation, weight gain, tremor, lethargy, disturbance in
attention, and peripheral oedema, whereas signifi-
cantly more patients treated with Lam reported in-
somnia, irritability, and arthralgia. The most frequent
adverse events tended to begin early in the course
of treatment. For instance, 81 % of the OFC-treated
patients and 85 % of the Lam-treated patients who
experienced somnolence experienced it within the
first 3 wk of treatment. Of the 43 OFC-treated patients,
33 % of the somnolence episodes were still ongoing
when the patient discontinued the study. Similarly,
this was the case for 32 % of the 19 Lam-treated
patients. Of those remaining patients in which length
of somnolence could be ascertained, 62 % of the OFC-
treated and 46 % of the Lam-treated patients’ episodes
lasted <3 wk, 28 % of the OFC-treated and 46 % of
the Lam-treated patients’ episodes lasted between
3 wk and 2 months, and the remaining (10 % OFC, 8 %
Lam) lasted >2 months. Increased appetite (78 % and
79 %, respectively), dizziness (74 % and 69 %), dry
mouth (94 % and 83 %), headache (77 % and 55 %), and
sedation (90 % and 84 %) also tended to occur within
the first 3 wk of treatment. Other adverse events ten-
ded to start throughout the duration of therapy and
not necessarily in the first weeks, with 42 % of the
 Olanzapine+fluoxetine vs. lamotrigine in bipolar depression 779

Table 3. Treatment-emergent adverse events, incidence >5 % (11/144), p=0.006], ALT [OFC 12.0 % (18/150) vs. Lam
in either group 4.9 % (7/144), p=0.036], and AST [OFC 8.3 % (13/156)
vs. Lam 2.1 % (3/145), p=0.019]. There were five
Adverse event OFC ( %) Lam ( %) p value OFC- and two Lam-treated patients with treatment-
emergent high-fasting glucose (p=0.447). There was a
Weight increased 22.4 2.9 <0.001 significantly greater incidence of potentially clinically
Somnolence 21.0 9.3 0.001 relevant weight gain as defined by an increase of o7 %
Increased appetite 19.5 9.3 0.005 in weight in OFC-treated patients (OFC 33.8 % vs. Lam
Dry mouth 17.1 5.9 <0.001
2.1 %, p<0.001).
Dizziness 14.6 9.3 0.127
Sedation 14.1 2.9 <0.001
Headache 12.7 10.8 0.645 Discussion
Tremor 10.7 1.5 <0.001
Fatigue 9.3 6.9 0.468 To our knowledge this is the first randomized, double-

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Nausea 7.8 11.3 0.244 blind, direct comparison of OFC with Lam for the
Anxiety 7.3 6.9 1.00 ‘long-term ’ treatment of bipolar I depression. OFC-
Insomnia 5.9 14.7 0.003 treated patients had significantly greater improvement
Diarrhoea 5.9 5.9 1.00 in overall symptom severity and in depressive and
Lethargy 5.9 1.5 0.032 manic symptoms over 25 wk compared to Lam-treated
Rash 5.4 8.8 0.184 patients. More treatment-emergent adverse events and
Back pain 5.4 5.9 0.834
greater incidence of weight gain and hypercholestero-
Constipation 5.4 3.9 0.640
laemia, however, were documented for the OFC-
Upper respiratory 5.4 3.4 0.471
treated patients.
Disturbance in attention 5.4 1.0 0.020
Peripheral oedema 5.4 0 <0.001 In the previously reported 7-wk acute phase of this
Irritability 2.9 7.4 0.046 study (Brown et al. 2006), OFC-treated patients had
Arthralgia 1.5 5.9 0.019 significantly greater and more rapid improvement in
depressive symptoms and overall symptomology
OFC, Olanzapine/fluoxetine combination ; Lam, lamotrigine. compared to Lam-treated patients. A concern was that
much of this treatment difference may have been the
result of Lam’s slow dose titration. The present ex-
OFC-treated patients and 67 % of the Lam-treated
tension data support a small but real treatment differ-
patients who experienced weight gain, 50 % and 47 %
ence in favour of OFC for the continued improvement
(respectively) who experienced insomnia, and 75 %
of depressive and manic symptoms in patients with an
and 39 % who experienced nausea experiencing them
acute episode of bipolar I depression. Response rates
within the first 3 wk of treatment.
for OFC (68.8 %) and Lam (59.7 %) were not statisti-
There was one suicide attempt (week 13) and
cally different but were higher than that previously
two suicidal ideations (one with hospitalization) in
reported for either in the acute treatment of bipolar I
the OFC-treated patients, and three suicide attempts
depression (Calabrese et al. 1999 ; Tohen et al. 2003).
(weeks 1, 3, 17) and five suicidal ideations (one of
In addition, patients in both treatment groups main-
these patients also attempted suicide) (weeks 1, 2, 3, 5,
tained antidepressant response well. Relapse rates for
21) in the Lam-treated patients.
depressive episodes were 13.2 % for OFC-treated
patients and 16.0 % for Lam-treated patients. Rates of
Metabolic parameters
treatment-emergent mania were low for both groups
Clinically relevant laboratory values are reported in (OFC 5.0 % vs. Lam 7.3 %), consistent with the acute
Table 4. Laboratory samples were collected in a fasting data.
state. There were significant treatment differences in OFC-treated patients had significantly more ad-
the mean change to endpoint for weight, haemoglobin verse events. Importantly, with both treatments, many
A1c, prolactin, cholesterol, and LDL cholesterol in of the most frequent adverse events (somnolence, in-
favour of Lam. There were also significant treatment creased appetite, dry mouth, dizziness, sedation, and
differences for the incidence of treatment-emergent, headache) tended to occur within the first 3 wk of
abnormally high values for cholesterol [OFC 15.9 % treatment. Other adverse events such as weight gain
(23/145) vs. Lam 3.7 % (5/135), p<0.001], triglycerides and insomnia were reported throughout the 25-wk
[OFC 37.1 % (43/116) vs. Lam 13.4 % (13/97), p< trial. The incidence of nausea appeared to vary by
0.001], prolactin [OFC 18.5 % (29/157) vs. Lam 7.6 % treatment. Most OFC-treated patients reported nausea
780 E. Brown et al.

Table 4. Change from baseline to endpoint (LOCF) in laboratory values

Baseline, Mean change to

Item Treatment n mean (S.D.) endpoint (S.D.) p value

Weight (kg) OFC 201 83.4 (25.0) 4.4 (5.2) <0.001

Lam 190 84.7 (22.1) x0.9(4.3)
Fasting glucose (mg/dl) OFC 142 91.5 (16.3) 0.4 (12.5) 0.344
Lam 136 91.8 (11.9) x0.8 (12.1)
HgbA1c ( %) OFC 172 5.3 (0.5) 0.02 (0.4) 0.010
Lam 160 5.3 (0.4) x0.07 (0.3)
Prolactin (ng/ml) OFC 172 12.4 (13.4) 7.3 (21.0) <0.001
Lam 160 12.2 (10.6) 0.10 (11.0)
Cholesterol (mg/dl) OFC 170 198.3 (46.1) 13.9 (32.5) <0.001

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Lam 155 198.2 (41.0) x6.0 (29.0)
HDL cholesterol-dextran OFC 170 48.9 (14.6) 0.7 (10.8) 0.427
precipitation (mg/dl) Lam 155 47.0 (13.7) 0.2 (8.8)
LDL cholesterol (mg/dl) OFC 161 120.2 (39.7) 7.2 (28.7) <0.001
Lam 144 121.3 (35.4) x6.8 (25.8)
Triglycerides (mg/dl) OFC 170 138.9 (77.8) 40.0 (114.6) <0.001
Lam 155 157.1 (121.7) x14.6 (112.8)

LOCF, Last observation carried forward ; S.D., standard deviation ; OFC, olanzapine/duloxetine combination ; Lam, lamotrigine.

within the first 3 wk, whereas Lam-treated patients
reported nausea throughout the study.
OFC safety in this study appeared similar to what
has previously been reported regarding OFC for the
treatment of bipolar disorder (Corya et al. 2003 ; Tohen
et al. 2003). There was a significantly greater incidence
of treatment-emergent abnormally high prolactin
levels for OFC-treated patients compared with Lam-
treated patients. However, there were no prolactin-
related adverse events in patients who had high
prolactin levels at any time during the study. The in-
cidence of abnormally high prolactin values in OFC-
treated patients in the current study is consistent with
the incidence in trials of Olz (Crawford et al. 1997).
OFC-treated patients had significantly more mean
weight gain and increases in plasma cholesterol, tri-
glycerides, and prolactin compared with Lam-treated
patients. These increases must be considered along
with potential efficacy advantages in order to make
appropriate risk/benefit assessments for patients.
This study had a number of potential limitations. As
previously noted, Lam-treated patients did not receive
the target 200 mg/d dose until week 5 due to the slow
dose titration in accordance with its package insert
recommendation. Thus, the apparent more rapid re-
sponse with OFC may have been influenced by Lam’s
slow dose titration. However, patients were receiving
50 mg/d Lam starting at week 2 ; at 50 mg/d Lam has
been shown to be effective compared with placebo in a
7-wk study of acute bipolar I depression (Calabrese
et al. 1999). An additional limitation is the lack of a
placebo group. This may have lead to elevated re-
sponse rates for either or both treatments as well as
potentially reduced treatment differences.
In summary, OFC therapy produced significantly
greater improvement in overall severity of illness and
depressive symptoms compared to Lam therapy in the
6-month treatment of patients with acute bipolar I
depression. Response was well maintained in both
treatment groups, with no treatment difference in the
incidence of relapse. The incidence of treatment-
emergent mania was also low, and not statistically
significantly different between the treatment groups.
OFC-treated patients experienced significantly greater
weight gain and increases in cholesterol and trigly-
cerides compared to Lam-treated patients.
Acknowledgements
This study was funded by Eli Lilly and Company.
Acknowledgement is given to Stacia L. Mellinger and
Heather Fox for their editorial assistance in the prep-
aration of the manuscript.
Statement of Interest
Authors Brown, Adams, Degenhardt, Tohen and
Houston are employees of Eli Lilly and Company.
Dr Dunner has received grant support from Eli Lilly,
Pfizer, GlaxoSmithKline, Wyeth, Cyberonics, Merck,
 Olanzapine+fluoxetine vs. lamotrigine in bipolar depression
Janssen, and Forest ; has served as a consultant for
and/or on advisory boards for Eli Lilly, Pfizer,
GlaxoSmithKline, Wyeth, Bristol–Myers Squibb,
Cypress, Corcept, Janssen, Novartis, Shire, Somerset,
Otsuka, and Roche Diagnostics ; and has served on
speakers’ bureaux for Eli Lily, Pfizer, GlaxoSmith-
Kline, Wyeth, Bristol–Myers Squibb, Organon, and
Forest. Dr McElroy is a consultant to or serves on the
advisory boards of Abbott, Eli Lilly, GlaxoSmithKline,
Janssen, Ortho-McNeil, and Wyeth–Ayerst ; and is a
principal or co-investigator on research studies spon-
sored by AstraZeneca, Bristol–Myers Squibb, Esai, Eli
Lilly, Forest, National Institute of Mental Health
(NIMH), Ortho-McNeil, Pfizer, Sanofi-Synthelabo,
and Somaxon. Dr Keck is a consultant to or serves
on the advisory boards of Abbott, AstraZeneca,
Bristol–Myers Squibb, GlaxoSmithKline, Janssen,
Eli Lilly, Memory, Neurocrine Biosciences, Ortho-
McNeil, Pfizer, and Shire ; and is a principal or co-
investigator on research studies sponsored by Abbott,
the American Diabetes Association, AstraZeneca,
Bristol–Myers Squibb, GlaxoSmithKline, Eli Lilly,
Janssen, Merck, NIMH, National Institute of Drug
Abuse, Organon, Ortho-McNeil, Pfizer, the Stanley
Medical Research Institute, and UCB Pharma.
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