A double-blind, randomized,
placebo-controlled, active reference study
of Lu AA21004 in patients with major
Enric Alvarez1,2, Victor Perez1,2, Marianne Dragheim3, Henrik Loft3and Francesc Artigas2,4
1Servei de Psiquiatrı ´a, Hospital de Sant Pau, Universidat Autonoma de Barcelona, Barcelona, Spain
2Ministry of Science and Innovation (CIBERSAM)
3H. Lundbeck A/S, Copenhagen, Denmark
4Institut d’Investigacions Biomediques de Barcelona, CSIC, Barcelona, Spain
The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in
patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel
antidepressant that is a 5-HT3and 5-HT7receptor antagonist, 5-HT1Areceptor agonist, 5-HT1Breceptor
partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site
study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg
venlafaxine XR. All patients had a baseline Montgomery–A˚sberg Depression Rating Scale (MADRS) total
score o30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity
using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was
statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score
at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9
(5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to
placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) – placebo: four
(4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The
most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes
over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study,
treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients
Received 21 March 2011; Reviewed 3 May 2011; Revised 27 May 2011; Accepted 3 June 2011;
First published online 18 July 2011
Key words: Depression, Lu AA21004, MADRS, serotonin receptor affinity, venlafaxine.
phenyl]-piperazine) is a novel compound under de-
velopment as an antidepressant (Bang-Andersen et al.
2011) with affinity for the human 5-HT1A, 5-HT1B,
5-HT3and 5-HT7receptors and the 5-HT transporter
(SERT) (Moore et al. 2008). Based on preclinical data,
these affinities are considered to be of clinical rel-
evance and involved in the mechanism of action at
therapeutic doses. In vivo, Lu AA21004 increases the
extracellular levels of serotonin (5-HT), noradrenaline,
dopamine, acetylcholine and histamine in rat pre-
frontal cortex and hippocampus (Moore et al. 2008).
Lu AA21004 is extensively metabolized in the liver
and at least five cytochrome P450 isoenzymes appear
to be involved. The metabolism of Lu AA21004 to
its major metabolite (pharmacologically inactive) is
mediated primarily by CYP2D6. In addition, Lu
AA21004 does not seem to be a clinically relevant
inhibitor or inducer of cytochrome P450 isoenzymes.
Address for correspondence: Dr M. Dragheim, ICR Mood & Anxiety
Disorders, H. Lundbeck A/S, Ottliavej 9, DK-2500 Valby, Denmark.
Tel.: +45 308 32016 Fax: +45 364 38215
Some of the data in this article were presented in a poster at the
162nd Annual Meeting of the American Psychiatric Association,
16–21 May 2009, San Francisco, CA, USA.
The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons
Attribution-NonCommercial-ShareAlike licence <http://creativecommons.org/licenses/by-nc-sa/2.5/>. The written permission of
Cambridge University Press must be obtained for commercial re-use.
International Journal of Neuropsychopharmacology (2012), 15, 589–600. f CINP and Cambridge University Press 2011
The terminal elimination half-life after multiple doses
is estimated at y60–70 h. The exposure (Cmaxand area
under curve) increased linearly with dose (2.5–60 mg).
The absorption of Lu AA21004 is independent of
food intake (Wang et al. 2009) and maximum plasma
concentrations are reached 3–16 h after dosing. The
rationale for choosing the Lu AA21004 doses (5 and
10 mg) in this proof-of-concept study was based on
non-clinical and phase I data. Approximately 60–80%
occupancy of the human SERT is required to achieve a
therapeutic effect with selective serotonin reuptake
inhibitors (SSRIs) or serotonin noradrenaline reuptake
inhibitors (SNRIs) (Meyer, 2007). In contrast, an occu-
pancy level of 41% with Lu AA20004 in rats led to a
significant increase in extracellular levels of 5-HT,
perhaps due to the additional pharmacological activi-
ties of Lu AA21004, which may counteract negative
feedback mechanisms operating at cellular and net-
work levels. The dose of 5 mg/d corresponds to a
SERT occupancy of y40% in human brain and was,
therefore, expected to be an effective dose (Areberg
et al. 2009).
The aim of this phase II clinical study was to inves-
tigate the efficacy, safety, and tolerability of two fixed
doses (5 and 10 mg/d) of Lu AA21004 vs. that of
placebo after 6 wk treatment in adult patients with
major depressive disorder (MDD). Venlafaxine XR
(225 mg/d) was used as the active reference.
This randomized, double-blind, fixed-dose, placebo-
controlled, active reference study recruited 429 ran-
domized patients from 49 psychiatric settings in
11 countries (Australia, Austria, Canada, Czech
Republic, Finland, France, Italy, Malaysia, Slovakia,
Spain, Sweden). Outpatients with MDD were re-
cruited from psychiatric settings from August 2006 to
August 2007. Advertisements were used in Australia,
Austria, Canada, Finland, Malaysia, and Sweden. The
study was conducted in accordance with the prin-
ciples of Good Clinical Practice (ICH, 1996) and the
Declaration of Helsinki (WMA, 1964). Local ethics
committees approved the study design and eligible
patients gave their written informed consent before
(1:1:1:1) to one of the four treatment arms for a 6-wk
double-blind treatment period. Randomized patients
were given 1-wk wallet cards at each visit and were
instructed to take two capsules per day, orally, at the
same time every day (preferably in the morning). Lu
AA21004 was dosed at 5 or 10 mg/d for 6 wk and
venlafaxine at 75 mg/d for 4 d, 150 mg/d for the fol-
lowing 3 d, and 225 mg/d for the remainder of the
treatment period. Efficacy and tolerability were as-
sessed at screening, baseline and after 1, 2, 3, 4, 5, and
6 wk. Patients who completed the 6-wk double-blind
treatment period entered a 2-wk double-blind taper
period. During this period, patients on 5 mg/d Lu
AA21004 switched to placebo; patients on 10 mg/d Lu
AA21004 received 5 mg/d Lu AA21004 for the first
week (week 7) and placebo for the second week
(week 8); patients on placebo remained on placebo;
patients on venlafaxine received 150 mg/d venlafax-
ine for the first week (week 7) and 75 mg/d for the
second week (week 8). Patients were contacted for a
safety follow-up 4 wk after the completion visit.
Down-taper medication was also offered to patients
Main entry criteria
Patients with MDD presenting with a current major
depressive episode according to DSM-IV-TR criteria
(APA, 1994) were included in the study if they were an
outpatient of either sex, aged from 18 yr to 65 yr, with
a Montgomery–A˚sberg Depression
(MADRS) (Montgomery & A˚sberg, 1979) total score
o30 at the baseline visit.
Patients were excluded if they had any current
psychiatric disorder other than MDD as defined in
DSM-IV-TR [assessed using the Mini International
Neuropsychiatric Interview (MINI; Sheehan et al.
1998)], or if they had a current or past history of manic
or hypomanic episode, schizophrenia or any other
psychotic disorder, including major depression with
psychotic features, mental retardation, organic mental
disorders, or mental disorders due to a general medi-
cal condition, any substance abuse disorder within the
previous 6 months, presence or history of a clinically
significant neurological disorder (including epilepsy),
any neurodegenerative disorder, or any Axis II dis-
order that might compromise the study.
Patients at serious risk of suicide, based on the in-
vestigator’s clinical judgement, or who had a score of
o5 on item 10 of the MADRS scale (suicidal thoughts)
were also excluded, as were those receiving formal
behaviour therapy or systematic
or were pregnant or breastfeeding, had a known
hypersensitivity or were non-response to venlafaxine,
or whose current depressive symptoms were con-
sidered by the investigator to have been resistant
to two adequate antidepressant treatments of at least
6 wk duration, or had previously been exposed to
590 E. Alvarez et al.
Patients were also excluded if they were taking the
following psychotropic drugs within 2 wk prior to
baseline or during the study: Reversible or irreversible
monoamine oxidase inhibitors, SSRIs (fluoxetine
within 5 wk), SNRIs, tricyclic antidepressants, psy-
choactive herbal remedies, any drug used for aug-
mentation of antidepressant action or any other
antidepressant drugs, oral antipsychotic and anti-
manic drugs, or dopamine antagonists, any anxiolytics
(including benzodiazepines); and any anticonvulsant
drug, serotonergic agonists, narcotic analgesics or
cough agents, anti-arrhythmics, oral anticoagulants,
proton pump inhibitors, steroids, cisapride, macrolide
all anti-inflammatory agents, anti-migraine agents,
pseudoephedrine, hypolipidaemics, and episodic use
of insulin. Occasional use of zolpidem, zopiclone and
zaleplon for insomnia was allowed.
Patients were withdrawn if they became pregnant
during the study, if the investigator considered it to be
in the best interest of the patient for safety/efficacy
reasons, if laboratory values were outside normal
ranges and clinically significant, if they were con-
sidered to be at significant risk of suicide, if they
scored o5 points on item 10 (suicidal thoughts) of the
MADRS, if the randomization code for a patient was
broken, if consent to participate was withdrawn, if
they did not take study medication for more than
6 consecutive days, or if the patient was lost to follow-
up. The patient could be withdrawn from the study
if a serious adverse event (SAE) occurred. If adverse
events (AEs) were contributory to withdrawal, they
were always regarded as the primary reason for
Patients were evaluated using the MADRS from
baseline to week 6. Rater training was undertaken to
increase inter-rater reliability, and was chaired by an
experienced investigator. Only those investigators
who had actively participated in rater training ses-
sions prior to inclusion of patients into the study and
had received rater certification were allowed to rate
patients. Patient ratings were assessed by the same
investigator at each visit, whenever possible.
Allocation to treatment
The medication was given as capsules of identical ap-
pearance. Patients who met the selection criteria at the
baseline visit were assigned to double-blind treatment
according to a computer-generated randomization list.
The details of the randomization series were unknown
to any of the investigators and were contained in a set
of sealed opaque envelopes. At each study site,
sequentially enrolled patients were assigned the low-
est randomization number available in blocks of four.
All investigators, study personnel and participants
were blinded to treatment assignment for the duration
of the entire study. The randomization code was bro-
ken for one patient (accidentally) who had completed
the study before this was discovered, and was there-
fore not withdrawn from the study.
All safety analyses were based on the all-patients-
patients who took at least one dose of study medi-
cation. All efficacy analyses were based on a modified
intent-to-treat set (ITT) – the full-analysis set (FAS),
comprising all patients in the APTS who had at least
Power and sample size calculations
It was planned to randomize a minimum of 384
patients with a DSM-IV-TR diagnosis of a major de-
pressive episode (MDE) into the double-blind period
of the study. With 96 patients in each treatment group
and a standard deviation (S.D.) of 9 points, the power
to detect a true treatment effect of 3.7 points on the
MADRS total score at week 6, using last observation
carried forward (LOCF), would be 80%.
Primary efficacy analysis
Four hypotheses were part of the primary efficacy
analysis, which was fully adjusted for multiplicity
using a hierarchical testing procedure at the 5% level
of significance as long as the previous hypothesis was
rejected. The order of testing was: no difference be-
tween the 10 mg dose vs. placebo at week 6, no differ-
ence between 5 mg vs. placebo at week 6, no difference
between 10 mg dose vs. placebo at week 1, and finally
no difference between 5 mg dose vs. placebo at week 1.
The statistical model was an analysis of covariance
(ANCOVA) of the change from baseline in MADRS
total score (FAS, LOCF) with treatment and site as
fixed factors and the baseline MADRS score as a co-
variate. The primary efficacy analysis was repeated on
observed cases (OC) data, using both an ANCOVA
and a mixed model for repeated measurements
Secondary efficacy analysis
Prospectively defined secondary clinician-rated vari-
ables were: MADRS total score, 24-item Hamilton
Lu AA21004 for treatment of MDD 591
Depression (HAMD24) total score (Hamilton, 1960),
Clinical Global Impression – Improvement (CGI-I)
and Clinical Global Impression – Severity (CGI-S)
scores (Guy, 1976), Hamilton Anxiety (HAMA) total
score (Hamilton, 1959), remission [defined as MADRS
f10, 17-item HAMD (HAMD17) f7 or as a CGI-S
score f2] and response (defined as o50% decrease
from baseline in MADRS or HAMD24total score, or a
CGI-I score f2) at all time points.
The change from baseline to each visit in all the
secondary efficacy variables, except response and re-
mission, was analysed using an ANCOVA, adjusting
for baseline score, site, and treatment, using both
OC and LOCF data. For CGI-I, the baseline CGI-S
score was used for adjustment. The change from
baseline to each visit in all the secondary efficacy
variables, except response and remission, was also
analysed using MMRM to compare the treatment
groups over all assessment points simultaneously
using OC data.
Response and remission rates for each visit were
evaluated using Fisher’s exact test. The CGI-S and
CGI-I scores were analysed at the last visit (OC and
LOCF) using ANCOVA. Unless otherwise stated, the
terms ‘significant’ and ‘significantly’ refer to statisti-
cal significance at the 5% level, two-sided. Efficacy
analyses that were not multiplicity-controlled were
considered secondary. The principal statistical soft-
ware used was SAS1version 9.1 (SAS Institute Inc.,
Each patient was asked a non-leading question
(such as, ‘how do you feel?’) at each visit, starting
at baseline. All AEs (including any change in concur-
rent illnesses or new illnesses) either observed by
the investigator or reported spontaneously by the
patient were recorded. AEs were coded using the
lowest level term according to the Medical Dictionary
for Regulatory Activities, version 10.0. The time to
withdrawal due to AEs was analysed using the Cox
model. The incidences of individual AEs were com-
pared between the treatment groups using Fisher’s
As a post-hoc analysis, the safety database was
searched at preferred-term and verbatim-term level
for possible suicide-related AEs, as described by the
FDA (Laughren, 2006).
Patient baseline characteristics
The APTS comprised 426 patients (placebo, 105;
venlafaxine, 113; 5 mg Lu AA21004, 108; 10 mg Lu
AA21004, 100) (Fig. 1). Slightly more patients than
planned were enrolled in the study, raising the power
from 80% to 84%. There were no clinically relevant or
statistically significant differences between the treat-
ment groups in patient demographics or clinical
characteristics at baseline (Table 1). Patients had a
105 108 100426 113
105108 100 425112
87 9882 36093
Ven 225Lu AA21004 5Lu AA21004 10Total
Fig. 1. Flow chart of patient disposition. AE, Adverse events, ITT, intention to treat; LoE, lack of efficacy; MADRS,
Montgomery–A˚sberg Depression Rating Scale; PBO, placebo; Ven 225, venlafaxine XR 225 mg.
592E. Alvarez et al.
mean age (¡S.D.) of 43.3¡11.5 yr, 62.7% were women,
and 92.0% were Caucasian.
The mean baseline MADRS total score was 34.0,
indicating a severely depressed patient population,
consistent with the mean CGI-S score of 5.1. Patients
were diagnosed with their first MDE y10 yr prior to
enrolment. Between 74% and 80% of the patients in
each treatment group had had a previous MDE and
their current episode had started about 5 months prior
to enrolment (Table 1). There was a substantial level of
anxiety symptoms, as indicated by a mean baseline
HAMA total score of 22.2. About 40% (range 36–41%)
of the patients in each treatment group had a concur-
rent medical condition. The number of patients taking
zolpidem, zopiclone, or zaleplon prescribed episodi-
cally for insomnia was similar for placebo (n=3),
venlafaxine (n=6), 5 mg Lu AA21005 (n=3), and
10 mg Lu AA21005 (n=3). Between 21% and 33% of
the patients took concomitant medication that they
continued with, and 26–29% commenced concomitant
medication during the study.
Withdrawals from the study
The withdrawal rate due to all reasons during the
entire study was 15% (Fig. 1), ranging from 9% (5 mg
Lu AA21004) to 18% (venlafaxine and 10 mg Lu
AA21004). More than 80% of the patients in each
treatment group completed the study (Fig. 1). There
was a slightly larger proportion of patients who
completed the study in the 5 mg Lu AA21004 group
than in the placebo, 10 mg Lu AA21004, or venlafaxine
groups. The proportions of patients who withdrew
due to AEs was statistically significantly different
between venlafaxine and placebo, but not between the
Lu AA21004 groups and placebo. There was an even
distribution of withdrawals for any reason over time
and no statistically significant differences between
the treatment groups, between men and women, or
between patients aged f50 or >50 yr. The median
compliance with study medication was 98%.
On the pre-defined primary efficacy endpoint, both
doses of Lu AA21004 were statistically significantly
(p<0.0001) superior to placebo in mean change from
baseline in MADRS total score at week 6 (FAS, LOCF),
with mean treatment differences to placebo of 5.9
(5 mg) and 5.7 (10 mg) points (Table 2) in a multi-
correspond to a standardized effect size (Cohen’s
d) of 0.56 (5 mg) and 0.54 (10 mg). Venlafaxine was
also statistically significantly (p<0.0001) superior to
placebo at week 6, with a mean treatment difference to
placebo of 6.4 points (LOCF). The estimated treatment
differences and nominal p values at week 6 obtained
from an analysis using MMRM were similar to those
Table 1. Baseline patient characteristics
5 mg (n=108)
Lu AA21004 10 mg
225 mg (n=113)
Patients with first MDE
Years since first MDE¡S.D.
Days since start of current MDE¡S.D.
MADRS total score¡S.D.
HAMA total score¡S.D.
69 (65.7%) 70 (64.8%)66 (66.0%)62 (54.9%)
aBased on the full-analysis set: CGI-S, Clinical Global Impression – Severity; HAMA, Hamilton Rating Scale for Anxiety;
HAMD24, Hamilton Rating Scale for Depression (24 items); MADRS,Montgomery–A˚sberg Depression Rating Scale; MDE, major
depressive episode; S.D., standard deviation.
Lu AA21004 for treatment of MDD 593
obtained in the ANCOVA analyses [5.6¡1.3 (5 mg
Lu AA21004), 7.2¡1.4 (10 mg Lu AA21004), 7.6¡1.3
(venlafaxine), all p<0.0001] (Table 2). As a sensitivity
analysis, the non-parametric Kruskal–Wallis test
showed a statistically significant difference between
the active treatments and placebo. The assumption of
homogeneity of variances across treatment groups
was confirmed using Bartlett’s test (p=0.90). At week
1, with a difference from placebo in the MADRS total
score of 0.8 for 10 mg (p=0.2377) and 0.2 for 5 mg
(p=0.7489), none of the active treatments separated
significantly from placebo.
Secondary efficacy analyses
The mean MADRS total score decreased in all active
treatment groups from 34.1 at baseline to y13.4 in the
LOCF analysis and to y10.9 in the OC analysis at
week 6. For Lu AA21004, a statistically significant
difference compared to placebo in the change from
baseline in MADRS total score, in favour of Lu
AA21004, was seen from week 2 (10 mg) or week 3
(5 mg) onwards (LOCF and OC). For venlafaxine, a
statistically significant difference to placebo was seen
from week 2 (OC) or week 3 (LOCF) onwards (Fig. 2).
At week 6, the proportion of MADRS responders
(patients with o50% decrease in MADRS total score)
and remitters (MADRS score f10) was statistically
significantly higher in all active treatment groups than
placebo (LOCF and OC) (Table 3). Single item analysis
at week 6 showed a statistically significant advantage
for both doses of Lu AA21004 for 9 out of the 10 items
(except for ‘concentration difficulties’) relative to
The mean HAMD24total score decreased in all active
treatment groups from 29.5 at baseline to y11.7 in the
LOCF analysis and y9.7 in the OC analysis at week 6
Mean change from baseline (MADRS)
Lu AA21004 5 mg (n=108)
Lu AA21004 10 mg (n=100)
Fig. 2. Mean change from baseline in Montgomery–A˚sberg
Depression Rating Scale (MADRS) total scores (ANCOVA,
FAS, OC, over time) and LOCF (week 6). * p<0.05, ** p<0.01,
*** p<0.001 vs. placebo. FAS, Full-analysis set; LOCF, last
observation carried forward; OC, observed cases.
Table 2. Change from baseline in MADRS total score at week 6 (FAS)
Analysis Treatment groupMean¡S.E.
to placebop value
Lu AA21004 5 mg (n=108)
Lu AA21004 10 mg (n=100)
Lu AA21004 5 mg (n=99)
Lu AA21004 10 mg (n=83)
MMRM Placebo (n=88)
Lu AA21004 5 mg (n=99)
Lu AA21004 10 mg (n=83)
FAS, Full-analysis set; LOCF, last observation carried forward; MADRS,
Montgomery–A˚sberg Depression Rating Scale; MMRM, mixed model repeated
measures; OC, observed cases; S.E., standard error of the mean.
594 E. Alvarez et al.
(Table 4). For Lu AA21004 (5 mg and 10 mg), a
statistically significant difference to placebo was seen
from week 1 onwards. For venlafaxine, a statistically
significant difference to placebo was seen from week 2
(OC) or week 3 (LOCF) onwards. At week 6, the pro-
portion of HAMD24responders (patients with o50%
decrease in HAMD24 total score) and remitters
(HAMD17 score f7) was statistically significantly
higher in all active treatment groups compared to
placebo (LOCF and OC) (Table 3).
The level of anxiety symptoms, as assessed by the
mean HAMA total score decreased in all active
treatment groups from y22 at baseline to y10.1 in the
LOCF analysis (Table 4) and y8.4 in the OC analysis
at week 6. For Lu AA21004, a statistically significant
difference to placebo was seen in change from baseline
in HAMA total score from week 2 (10 mg, OC) or week
3 (LOCF and OC) onwards (Fig. 3). For venlafaxine,
a statistically significant difference to placebo was seen
from week 3 (OC) or week 4 (LOCF) onwards.
The mean CGI-S score decreased in all active treat-
ment groups from y5.2 at baseline to y2.6 in the
LOCF analysis (Table 4) and y2.3 in the OC analysis
at week 6. The mean CGI-I score improved in all active
Table 3. Proportion (%) of responders and remitters at week 6 (FAS, mean)
5 mg (n=108)
10 mg (n=100)
225 mg (n=112)
LOCFOC LOCFOCLOCF OC LOCFOC
CGI-S, Clinical Global Impression – Severity; CGI-I, Clinical Global Impression – Improvement; HAMD17, Hamilton Rating
Scale for Depression (17 items); HAMD24, Hamilton Rating Scale for Depression (24 items); FAS, full-analysis set;
LOCF, last observation carried forward; MADRS, Montgomery–A˚sberg Depression Rating Scale; OC, observed cases.
*p<0.05, ** p<0.01, *** p<0.001 vs. placebo.
Table 4. Mean change from baseline in efficacy variables at week 6, difference to placebo (FAS)
LOCF, ANCOVA OC, ANCOVA MMRM
Ven5 mg 10 mg 5 mg10 mg5 mg10 mg
CGI-S, Clinical Global Impression – Severity; CGI-I, Clinical Global Impression – Improvement; FAS, full-analysis set; HAMA,
Hamilton Rating Scale for Anxiety; HAMD24, Hamilton Rating Scale for Depression (24 items); LOCF, last observation carried
forward; MADRS, Montgomery–A˚sberg Depression Rating Scale; OC, observed cases; MMRM, mixed model repeated
measures; Ven, venlafaxine.
Lu AA21004 for treatment of MDD595
treatment groups to y2.0 at week 6 (LOCF, Table 4).
For Lu AA21004, a statistically significant difference to
placebo was seen in mean CGI-I score from week 1
(10 mg) or week 2 (5 mg) onwards (LOCF). For venla-
faxine, a statistically significant difference to placebo
was seen from week 3 onwards (LOCF). At week 6, the
proportion of CGI responders (CGI-I f2) and CGI
remitters (CGI-S f2) was statistically significantly
higher in all active treatment groups than placebo
(LOCF and OC) (Table 3).
Tolerability and safety
Since Lu AA21004 is a compound with a new mode of
action, its safety and tolerability profile is described in
some detail below. During the 6-wk treatment period,
approximately three-fifths of patients in the placebo
(61%) and 5 mg Lu AA21004 (68%) groups and ap-
proximately three-quarters of the patients in the 10 mg
Lu AA21004 (74%) and venlafaxine (75%) groups had
one or more AE. A total of 30 (7%) patients withdrew
due to AEs: four (4%) in the placebo group, three (3%)
in the 5 mg Lu AA21004 group, seven (7%) in the
10 mg Lu AA21004 group, and 16 (14%) in the venla-
faxine group. Only in the venlafaxine group, did stat-
istically significantly more patients withdraw due to
AEs than in the placebo group (p=0.009). Seven
patients withdrew from the study due to nausea: three
(3%) in the 10 mg Lu AA21004 group and four (4%) in
the venlafaxine group.
AEs reported by o5% of patients during the 6-wk
treatment period are shown in Table 5. The most
common AEs reported in the active treatment groups
were nausea, headache, hyperhidrosis, and dry
mouth. For Lu AA21004, nausea (5 and 10 mg), hyper-
hidrosis (10 mg), and vomiting (10 mg) were the
only AEs reported with an incidence statistically sig-
nificantly higher than placebo. For the majority of
patients reporting nausea, it was transient and mild or
moderate in intensity. In addition to nausea and hy-
perhidrosis, the incidence of dry mouth, constipation,
and anorgasmia were statistically significantly higher
in the venlafaxine group than placebo group.
In all treatment groups, the majority of patients who
had AEs, had mild or moderate AEs. The incidence
of severe AEs was 4% in the placebo group, 6% in the
Lu AA21004 groups, and significantly higher at 12%
in the venlafaxine group (p=0.026, Fisher’s exact).
Severe AEs reported by at least two patients in any Lu
AA21004 treatment group included: severe headache
by three patients (3%) in the 10 mg Lu AA21004 group
and two patients (1.9%) in the placebo group, and two
patients (1.9%) in the 5 mg Lu AA21004 group had
severe fatigue. In addition, severe AEs reported by
at least two patients in the venlafaxine group were:
severe nausea and severe vomiting, each reported by
two patients (1.8%), severe insomnia in four patients
(3.5%), severe dizziness in three patients (2.7%), and
severe hyperhidrosis in two patients (1.8%).
For patients treated with both Lu AA21004 doses,
the incidence of AEs related to sexual dysfunction
(anorgasmia, delayed ejaculation, erectile dysfunction,
decreased libido, impotence, abnormal organism,
abnormal sexual function) was at placebo level [1.9%
(5 mg) and 1.0% (10 mg) vs. 1.9% (placebo)]. In total,
23 AEs related to sexual dysfunction were reported by
18 patients, comprising seven women and 11 men. Of
the women (n=267), two were in the placebo group,
one from each of the Lu AA21004 groups, and three
from the venlafaxine group. Of the men (n=159),
all 11 were from the venlafaxine group, in which the
incidence of AEs related to sexual dysfunction was
statistically significantly higher than placebo (12.4%
vs. 1.9%, p=0.0033, Fisher’s exact test). Two patients
withdrew due to AEs related to sexual dysfunction;
one due to anorgasmia and 1 due to delayed ejacu-
lation, both from the venlafaxine group.
No possibly suicide-related AEs were found in the
database search during the entire study. A decrease
in MADRS item 10 score (suicidal thoughts) from
Mean change from baseline (HAMA)
Lu AA21004 5 mg (n=101)
Lu AA21004 10 mg (n=94)
Fig. 3. Mean change from baseline in Hamilton Rating Scale
for Anxiety (HAMA) total scores (ANCOVA, FAS, OC, over
time) and LOCF (week 6). * p<0.05, ** p<0.01, *** p<0.001
vs. placebo. FAS, Full-analysis set; LOCF, last observation
carried forward; OC, observed cases. Some patients were
excluded due to the use of a non-validated scale in France.
596E. Alvarez et al.
baseline was seen in all treatment groups at all weeks.
A numerical superiority over placebo was seen in all
active treatment groups from week 2 onwards.
No deaths occurred during the study. Three patients
had SAEs: two in the 10 mg Lu AA21004 group (one
patient with worsening of MDD, and one patient with
Varicella zoster infection) and one in the venlafaxine
group (brain tumour).
Vital signs, weight, clinical laboratory values, ECGs
No consistent trends were observed for vital signs,
weight, clinical laboratory values or ECG in the active
treatment groups, and there were no marked differ-
ences between patients receiving active treatment and
those receiving placebo. The incidence of potentially
clinically significant (PCS) values was generally low
and evenly distributed among the treatment groups
for vital signs, weight or clinical laboratory values, and
no patients withdrew due to a PCS value.
and the mean changes from screening were generally
small [f2 mmHg (supine diastolic blood pressure),
f5 mmHg (supinesystolic
f4 bpm (supine pulse)].
blood pressure), or
The mean weight change from baseline to week 6
was f¡0.3 kg in the Lu AA21004 and placebo groups
and x0.8 kg in the venlafaxine group, which was not
considered to be clinically relevant. Weight gain
(o7%) was recorded for one placebo patient and three
patients in the 10 mg Lu AA21004 group, whereas
weight loss (o7%) was recorded for two patients in
the 10 mg Lu AA21004 group, and one patient in the
venlafaxine group. No patients withdrew due to
The mean changes in clinical laboratory values were
small and similar between treatment groups and the
incidence of PCS values was generally <2% in any
treatment group for any laboratory test. No clinically
relevant abnormalities in ECG values were found after
administration of Lu AA21004.
This is the first double-blind, randomized, placebo-
controlled study to evaluate the efficacy, safety and
tolerability of Lu AA21004 in patients with MDD. The
active reference, venlafaxine XR (225 mg), was in-
cluded with the purpose of validating the study
methodology and patient population, and was effec-
tive on the primary efficacy analysis. Both doses of
Lu AA21004 resulted in a significant improvement
Table 5. Adverse events (AEs) with an incidence of o5% in any group in the 6-wk double-blind treatment period (APTS)
5 mg (n=108)
10 mg (n=100)
225 mg (n=113)
Patients with AEs
Ejaculation delayed (men)a
Erectile dysfunction (men)a
APTS, All-patients-treated set.
aNumber of men: n=36 (placebo), n=38 (5 mg), n=35 (10 mg), n=51 (venlafaxine).
*p<0.05, ** p<0.01, *** p<0.001 vs. placebo.
Lu AA21004 for treatment of MDD597
compared to placebo on the primary efficacy analysis.
It has been suggested (Moncrieff & Kirsch, 2005) that
the difference in total scores for an active treatment
vs. placebo can be driven by a few single individual
items in a rating scale. However, this is not the case in
the present study, in which both doses of Lu AA21004
showed significantly greater efficacy than placebo on
nine of the 10 MADRS items.
There is a large difference to placebo for all active
treatment groups of about 5–6 points on the HAMD24
(which translates to y4 points on the HAMD17), which
is more than the y2 points on the HAMD17seen in
FDA pivotal antidepressant studies (Kirsch et al. 2002).
This also confirms the assay sensitivity of the studied
population, who were not only severely depressed,
but also had a substantial level of anxiety symptoms at
baseline. At week 6, the proportion of MADRS re-
sponders (patients with o50% decrease in MADRS
total score) and remitters (MADRS score f10) was
statistically significantly greater in all active treatment
groups than in placebo (LOCF and OC). The difference
between active treatment and placebo of y6 points
on the MADRS translates into a clinically relevant
difference in response rates of between 22% and 32%
units, compared to an average of 16% units for anti-
depressants approved by the competent European
authorities (Melander et al. 2008). The robustness of
the results was also confirmed by the significantly
better outcome than placebo on HAMD24, HAMA,
CGI-I and CGI-S.
Several pharmacological mechanisms are likely to
account for the multimodal antidepressant action of
Lu AA21004. It has been estimated that an 80% occu-
pancy of the human SERT is achieved at standard
doses of SSRIs or SNRIs (Meyer, 2007). However,
5 mg Lu AA21004 occupies y40% of SERT sites,
suggesting the existence of additional mechanisms
involved in its therapeutic activity. Hence, SERT
blockade by SSRIs evokes a series of negative feedback
mechanisms that attenuate the increase in extracellular
(synaptic) concentration of 5-HT, including the acti-
vation of 5-HT1Aand 5-HT1Bautoreceptors on sero-
tonergic neurons (Artigas et al. 1996, 2001). The partial
agonist activity of Lu AA21004 at 5-HT1Breceptors
may therefore help counteract the inhibition of
terminal 5-HT synthesis and release evoked by 5-HT1B
receptor activation. Likewise, its full agonist activity at
human 5-HT1A receptors expressed in cell lines is
predicted to evoke a rapid desensitization of 5-HT1A
autoreceptors (Haddjeri et al. 2009), thereby normal-
izing serotonergic cell firing and 5-HT release. On the
other hand, given the presence of excitatory 5-HT3
receptors in GABAergic interneurons in cortical and
limbic areas (Morales et al. 1996; Puig et al. 2004), their
activation by 5-HT may induce a GABA-mediated in-
hibition of neurotransmitter release. In support of this
view, the 5-HT3receptor antagonist ondansetron aug-
ments the increase of extracellular 5-HT in the ventral
hippocampus induced by the SSRI paroxetine (Mørk
et al. 2009). Moreover, blockade of 5-HT7 receptors
has been shown to produce rapid antidepressant-
like effects in the rat in behavioural and electro-
physiological experimental paradigms (Mnie-Filali
et al. 2011). In addition to these effects on the 5-HT
system, the systemic administration of Lu AA21004
increases the extracellular concentration of dopamine,
noradrenaline and acetylcholine (Haddjeri et al. 2009),
an effect probably contributing to its antidepressant
Due to the profile of Lu AA21004, a hierarchical
procedure was used to test for onset of action at
week 1. Although not significant on the MADRS, Lu
AA21004 displayed onset of antidepressant action,
with significant improvement vs. placebo at week 1
onwards for both doses on HAMD24, and for the 10 mg
dose on CGI-I.
The proportion of patient withdrawals has been
used in recent years as an indirect index of drug
effectiveness in the real world (Kahn et al. 2008;
Lieberman et al. 2005; Trivedi et al. 2006). The analysis
of withdrawal rates in patients treated with Lu
AA21004 indicates a better tolerability profile com-
pared to the active reference, venlafaxine. Compared
to placebo, significantly more patients withdrew due
to AEs only in the venlafaxine group.
The most common AEs reported in the active treat-
ment groups were nausea, headache, hyperhidrosis,
and dry mouth. No possibly suicide-related AEs were
found. No consistent trends were observed for vital
signs, weight, clinical laboratory values or ECG in the
active treatment groups, and there were no marked
differences between patients receiving active treat-
ment and those receiving placebo.
Sexual dysfunction during antidepressant treat-
ment is one of the main reasons for the lack of com-
pliance (Kennedy & Rizvi, 2009). According to the
present data, the incidence of spontaneously reported
AEs related to sexual dysfunction was similar to
placebo in patients treated with either dose of Lu
AA21004. In the venlafaxine group, the incidence of
AEs related to sexual dysfunction was significantly
higher than that of placebo (12.4% vs. 1.9%). Unlike
SSRIs, Lu AA21004 also displays moderate to high
affinity for 5-HT1A, 5-HT1B, 5-HT3and 5-HT7receptors
(see above). There is limited information on the role of
these receptors on sexual drive, although the increase
598 E. Alvarez et al.
in plasma testosterone levels evoked in male rats by
the proximity of female rats is further enhanced by
the selective 5-HT3 antagonist ondansetron, which
suggests that 5-HT3receptor blockade may lead to an
enhanced sexual drive (Amstislavskaya & Popova,
The generalizability of results from this study to the
broad population of depressed patients, like most
randomized controlled trials, is limited by the in-
clusion and exclusion criteria. Patients aged <18 yr or
>65 yr were not included, nor were patients with
specified psychiatric or medical comorbidities, or
patients at risk of suicidal behaviour, nor those with
treatment-resistant depression or with mild to mod-
erate depression. The titration of venlafaxine XR, from
75 mg to 225 mg over 7 d, was according to the manu-
facturer’s instructions. Only one patient treated with
venlafaxine withdrew in the first week of treatment,
indicating that there was no bias due to early with-
drawals in this treatment arm.
In conclusion, treatment with 5 mg and 10 mg Lu
AA21004 for 6 wk in this proof-of-concept study was
well tolerated and efficacious in reducing depressive
and anxious symptoms in patients with MDD.
This study was sponsored by H. Lundbeck A/S. The
authors gratefully acknowledge the participation of
the following investigators at the psychiatric sites
in this study. Australia: Thomas George, Michael
Kasper, Margot Schmitz, Harald Schubert. Canada:
Javed Ali, David Bakish, Martin Tremblay, Raymond
Matte, Marie-Jose ´e Filteau. Czech Republic: Petr
Roc ˇek, Jiri Bilik, Jan Drahozal, Juraj Rektor, Michaela
Klabusayova, Erik Herman, Zdenek Solle. Finland:
Antti Ahokas, Anna Savela, Hannu Koponen, Riitta
Gailledreau, Francis Gheysen, Pierre Le Goubey,
Marcel Zins-Ritter, Paule Khalifa, Christian Gaussares,
Daniel Bonnaffoux. Italy: Giovanni Battista Cassano,
Pietro Bria. Malaysia: Teck-Hoe Yen, Sulaiman
Ahmad Hatim. Slovakia: Marek Zelman, Viera
Korinkova, Eva Janikova,
Molcan. Sweden: Ingemar Sjo ¨din, Eva Scheutz, Kurt
Wahlstedt, Anders Elverfors, Maj-Liz Persson, Angela
Marre ´-Lippitz. The authors thank D. J. Simpson
(H. Lundbeck A/S) for technical assistance in the
preparation of the manuscript. The authors are en-
tirely responsible for the scientific content of this
[Trial Registration: www.clinicaltrials.gov iden-
Statement of Interest
Over the past 2 years, E. A´lvarez has received con-
sulting and educational honoraria from Eli Lilly,
Sanofi-Aventis, Lundbeck, Pfizer; and has partici-
pated in clinical trials sponsored by Eli Lilly,
Bristol–Myers, Sanofi-Aventis, Servier and Lundbeck.
F. Artigas declares having received lecture fees from
CSC Pharmaceuticals and Lilly on antidepressant
drugs. Over the past 2 years, V. Perez has received
consulting and educational honoraria from Eli Lilly,
AstraZeneca, Sanofi-Aventis, Lundbeck, Pfizer; and
has participated in clinical trials sponsored by Eli
Lilly, Bristol-Meyers, AstraZeneca and Lundbeck.
employees of H. Lundbeck A/S, Denmark. The Editor-
in-Chief of this Journal, Dr Alan Frazer, serves on an
advisory board for Lundbeck that deals with the
mechanism of action of Lu AA21004. Consequently, he
removed himself from the review process, which was
handled exclusively by an appropriate Field Editor.
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