Psychopharmacology (2009) 207:213–223
DOI 10.1007/s00213-009-1649-6
ORIGINAL INVESTIGATION
Differential effects of escitalopram on attention:
a placebo-controlled, double-blind cross-over study
Barbara Drueke & Julia Baetz & Maren Boecker &
Olaf Moeller & Christoph Hiemke & Gerd Gründer &
Siegfried Gauggel
Received: 26 January 2009 / Accepted: 17 August 2009 / Published online: 16 September 2009
# Springer-Verlag 2009
Abstract
Rationale The role of serotonin (5-HT) in attention is not
fully understood yet.
Objective We aimed to investigate whether attention is
modulated after treatment with escitalopram, a selective
serotonin reuptake inhibitor (SSRI).
Methods We administered 10 mg of escitalopram to 20
healthy subjects in a placebo-controlled, double-blind
cross-over design for 1 day or to another 20 participants
for a period of 7 days. Attention was assessed at time of
plasma peak escitalopram concentration using the compu-
terised Attention Network Test (ANT), which is a combined
flanker and cued reaction time task.
Results The results showed differential effects of seroto-
nergic manipulation on attention depending on sequence of
intake. For the acute treatment, we found significant
differences between escitalopram and placebo for all
warning conditions dependent of sequence of intake:
participants receiving escitalopram as first treatment
B. Drueke (*) : J. Baetz : M. Boecker : S. Gauggel
Department of Medical Psychology and Medical Sociology,
RWTH Aachen University,
Pauwelsstr. 30,
52074 Aachen, Germany
e-mail: bdrueke@ukaachen.de
O. Moeller : G. Gründer
Department of Psychiatry and Psychotherapy
and JARA - Translational Brain Medicine,
RWTH Aachen University,
Pauwelsstr. 30,
52074 Aachen, Germany
C. Hiemke
Department of Psychiatry and Psychotherapy,
University of Mainz,
Untere Zahlbacher Str. 8,
55131 Mainz, Germany
showed significant slower reaction times in all warning
conditions as compared with placebo while participants
receiving escitalopram as second treatment showed signif-
icant faster reaction times as compared with placebo. For
the sub-chronic treatment, we found significant differences
between escitalopram and placebo depending on sequence
of intake, but only for the flanker condition: participants
receiving escitalopram first had significant slower reaction
times in incongruent trials with escitalopram as compared
with placebo while participants starting with placebo had
significant shorter reaction times in incongruent trials with
escitalopram.
Conclusions Thus, the results showed a differential effect
of escitalopram in cognition, especially in attention, and are
discussed with regard to an interaction between serotonin
and familiarity with the attention test.
Keywords 5-HT . Escitalopram . Attention .
Attention Network Test (ANT) . Humans
Introduction
Attention processes can be modulated by the action of
different neurotransmitters in the brain via administration of
specific psychotropic substances (Robbins 1997). Of special
interest is the neurotransmitter serotonin (5-HT) as it is
involved in different cognitive processes, e.g. learning and
memory (Riedel et al. 1999). Serotonin is also a critical
neurotransmitter in several mental disorders including major
depression and schizophrenia, which seem to be associated
with dysregulated 5-HT transmission and accompanied by
neurocognitive impairments. In schizophrenia for example,
serotonin receptors are increasingly recognised as major
targets for cognitive enhancement (Meltzer et al. 2003).
214
Indeed, second-generation antipsychotics such as clozapine
or risperidone, which are potent 5-HT2A receptor antagonists
(Meltzer 1999), are able to improve vigilance.
Various studies have demonstrated a modulating role for
serotonin in impulsivity and aggression (Hennig et al. 1997;
Hennig et al. 1998; Netter et al. 1999). In contrast, the role of
serotonin in attention is not fully understood yet. Animal
studies provide evidence for 5-HT influence on attention: the
selective 5-HT2A receptor antagonist M100907 improves
attentional performance in rats performing a five-choice serial
reaction time (5-CSRT) task (Mirjana et al. 2004). In contrast,
5-HT2A receptor agonists impair attentional functioning in rats
(Carli and Samanin 1992; Koskinen et al. 2000). In addition,
5-HT1A receptor agonists also impair rats’ accuracy in 5-
CSRT (Carli and Samanin 2000), while 5-HT1A antagonists
such as WAY100635 reduce attentional deficits induced by
cortical cholinergic dysfunction (Balducci et al. 2003).
In healthy volunteers, there is evidence that 5-HT
stimulation has a negative influence on attention processes.
Acute and subchronic oral administration of 20 and 40 mg
citalopram, a selective 5-HT reuptake inhibitor, led to an
impaired performance in the Mackworth Clock Test (MCT)
which is a measure for vigilance (Riedel et al. 2005).
Similar results for the MCT were also found by Schmitt et
al. (2002) with paroxetine, whereas the intake of 50 and
100 mg sertraline did not show any effect on vigilance
(Riedel et al. 2005). Further evidence for impairments of
attention performance by administering serotonergic drugs
comes from a study by Wingen et al. (2007). Wingen et al.
showed an impaired performance in a divided attention task
after administration of escitalopram (SSRI) alone and after
combined administration of escitalopram+pindolol (5-HT1A
antagonist) and escitalopram+ketanserin (5-HT2a antago-
nist), respectively, as compared with placebo. In contrast to
these findings, it is also postulated that SSRIs are able to
increase cerebral arousal, for example in the critical flicker
fusion threshold (CFFT), a task used for the assessment of
alertness, vigilance, and arousal. Acute and subchronic
administration of 20 mg citalopram (Nathan et al. 2000)
and 60 mg fluoxetine (Rammsayer and Netter 1988),
respectively, improved attention performance (i.e. performance
in the CFFT).
Taken together, results of animal and human studies
reveal inconsistent results regarding the role of the
serotonergic system in attention. Possible reasons for
inconsistent findings could be seen in the heterogeneity of
paradigms used to assess attention, differences in the
substances used (i.e. the potency for blocking 5-HT
reuptake), duration of drug administration (single vs.
multiple dosing) and dosages used. Therefore, the present
study investigated whether 5-HT release has an influence
on attention performance exerted by administration of a
highly selective 5-HT reuptake inhibitor (i.e. escitalopram)
Psychopharmacology (2009) 207:213–223
and a sophisticated measure of attention (i.e. Attention
Network Test (ANT); Fan et al. 2002) which allows a
detailed measurement of attentional functions via presenta-
tion of different cue and flanker conditions. We hypoth-
esised that an administration of 10 mg escitalopram should
have a selective influence on attention because 5-HT seems
to play a modulating role in cognition (Robbins and
Roberts 2007). However, no clear hypothesis can be
specified in regard to different attention components due
to inconsistent findings in the past. Therefore, we were not
only interested in the acute but also in the effects of sub-
chronic administration of escitalopram. We expected a
larger impact on attention performance after sub-chronic
treatment and therefore, we investigated the same hypothesis
for an effect on ANT performance after 7 days of treatment.
Materials and methods
A total number of (n=40) healthy male subjects aged
between 18 and 39 years participated in this study; 20 of
them received an acute treatment and another 20, a sub-
chronic treatment. Most of them were students. The means
and standard deviation for body weight (kilogram) and
height (centimetre) were 83.1±14.6 and 183.6±8.5 for the
acute treatment group and 87.1±18.1 and 181.4±5.3 for the
sub-chronic group, respectively. All participants were drug-
free and non-smokers and underwent a drug screening
before inclusion. To establish physical and mental health,
participants underwent a careful screening for any hormon-
al, cardiovascular or neurological diseases. This screening
was based on health questionnaires and interviews per-
formed by a physician. Furthermore, we analysed blood
samples of each participant to control physical health. In
addition, all participants underwent a semi-structured
clinical interview for mental disorders. Exclusion criteria
were a personal or family history of major mental or
neurological disorder in first-degree relatives, somatic
illness and regular alcohol or illicit drug abuse. No
participant had to be excluded due to any kind of acute or
chronic physical disease or mental disorder. All participants
were informed by a written study description on the aim of
the study, possible side effects, previous toxicology study
results and potential health risks. All participants gave their
written informed consent.
Challenge tests were performed at two sessions (placebo
and escitalopram) 1-week apart. Participants of the
multiple-doses group were also instructed about timing of
intake at home and how to handle problems during time of
intake. Furthermore, they were informed about the collec-
tion of a blood sample to control for their compliance
before starting the experiment on test day. Subjects received
detailed written instructions of what to do and what to
Psychopharmacology (2009) 207:213–223
avoid in the evening, night and morning before the
experiment. Instructions included for example: to go to
bed not later than midnight and to guarantee more than 6 h
of sleep, to avoid any medication as well as alcoholic or
caffeine-containing beverages etc. On the day of the
experiment, lunch was taken between 12:00 and 12:30 p.m.
Afterwards, no food intake was allowed.
The study was approved by the ethics committee of the
Medical Faculty of the RWTH Aachen University and the
National Institute for Drugs and Medical Devices and was
conducted in accordance with the Declaration of Helsinki.
Participants were paid and allowed to quit the study any
time they wished.
Design
The study was performed in a double-blind cross-over
design with two treatment levels (placebo and 10 mg
escitalopram [Cipralex®]) as a single or a repeated oral
dose: 20 participants received a single oral dose of 10 mg
escitalopram or placebo and another 20 participants
received 10 mg escitalopram or placebo for 7 days.
Participants were free to decide whether they would get
the short-term treatment (single intake) or the long-term
treatment (repeated intake). The participants were allocated
to their starting substance (placebo/escitalopram) at random,
but this was not fully counterbalanced for each length of
intake (1 vs. 7 days of intake). For the single intake, we
chose a time interval of 1 week between each session, and
for the multiple doses, we chose a time interval of 2 weeks
as it is sufficient for complete washout since the elimination
half-life of escitalopram is 27–32 h (Aronson and Delgado
2004). We decided to investigate sub-chronic effects after a
drug intake of 7 days as we expected a steady-state
concentration of escitalopram in plasma after five elimination
half-life times. Group size of 20 participants was based on a
power calculation (Faul et al. 2007).
Drugs
Escitalopram is a highly selective serotonin reuptake inhibitor
indicated for the treatment of major depressive disorder
(MDD), panic disorder, generalised anxiety disorder,
obsessive-compulsive disorder and social phobia (Burke
2002; Burke et al. 2002). Escitalopram is the therapeutically
active S-enantiomer of citalopram. Approved doses are 10–
20 mg as indicated by manufacturer Lundbeck (Copenhagen,
Denmark). Escitalopram has been shown to be an effective
and well-tolerated treatment for MDD in placebo-controlled
trials and to have a similar safety profile to citalopram
(Yevtushenko et al. 2007).
Possible side effects observed after escitalopram are
nausea, vertigo, reduced appetite, sleep disturbances, and
215
reduced libido. Maximal plasma concentrations have been
noted approximately 3–4 h after dosing (Sogaard et al.
2005). Escitalopram and placebo were administered as
white tablets of identical appearance and were provided by
H. Lundbeck A/S (Copenhagen, Denmark).
Experimental procedure
On the day of the tests (at 1:30 pm), participants were
seated in a comfortable chair in the laboratory. For
participants with 7-days intake plasma-concentration of
escitalopram were analysed from a blood sample to control
for compliance with drug administration. Blood samples
were analysed in the laboratory of the university hospital to
determine plasma concentrations of escitalopram. Drugs
were administered 15 min later (for all participants, 1-day
intake and 7-days intake) in identical tablets to guarantee
blindness for subjects and experimenters. After drug
administration, subjects were asked to complete different
personality questionnaires. At the time of expected plasma
peak (about 200 min after tablet intake) participants
performed the Attention Network Test (Fan et al. 2002).
Attention Network Test
The ANT is a computer-based choice reaction time (RT) task
which was designed for the assessment of reaction times
estimating alerting, orienting, and executive attention which
are proposed to describe functions of three attentional
networks (Fan et al. 2002). Subjects were required to
identify whether a central arrow presented on a computer
screen pointed left or right by pressing the equivalent button
on the keyboard always using the same hand. This target
arrow was flanked on either side by lines (neutral condition),
by two arrows in the same direction (congruent condition),
or in the opposite direction (incongruent condition). The
stimuli (one central arrow accompanied by four flankers)
appeared either above or below a fixation point. The three
conditions are depicted in Fig. 1.
There were four warning conditions indicating the
imminent appearance and/or location of the target: (1) no
cue (only fixation cross), (2) centre cue, (3) double cue and
(4) spatial cue (see Fig. 2 for details). The ANT is a
combination of the cued reaction time (Fernandez-Duque
Fig. 1 The three ANT target conditions
216
Fig. 2 The four ANT warning conditions
and Posner 1997) and the flanker task (Eriksen and
Ericksen 1974).
So, the ANT provides multiple conditions for the
measurement of attentional functions in a single task, and
it is possible to find out if reaction times are influenced by
alerting cues, spatial cues and flankers.
The ANT included a practise block with 24 trials and
three assessment blocks with 96 trials each (total duration,
30 min). During the practise block, the participants received
immediate feedback whether their response was right or
wrong or too slow. Each trial lasted exactly 4,000 ms and
consisted of five different periods. In the first period, a
fixation cross was presented for 400–1,600 ms. An
additional cue was then shown for 100 ms in the second
period followed by the fixation cross for 400 ms in the third
period. In the fourth period, the target arrow with flankers
was shown for at most 1,700 ms. After a response, the
fixation cross was presented again in the last period. The
duration of the last period depends on the duration of the first
fixation period and the reaction time (3,500 ms—first fixation
period—reaction time).
For data analysis, only valid trials and trials with a
reaction time between 200 and 2,000 ms were considered.
In addition, an outlier analysis was performed. Trials with a
reaction time two standard deviations above or below the
condition mean were not used for further analyses. In addition
to condition means, the overall mean reaction times as well as
the accuracy (percentage of correct responses) were recorded.
Statistics
All data were screened for deviation from normality,
outliers and homogeneity of variance. Since the study was
conducted in a cross-over design with two different treat-
ments (escitalopram vs. placebo) and two different admin-
istration durations (1-day intake vs. 7-days intake), we
conducted two analyses of variance (ANOVAs), one for the
acute treatment group and one for the group with sub-
chronic treatment. Dependent variables were the reaction
times in ANT conditions. For the first group (1-day intake),
Psychopharmacology (2009) 207:213–223
a four-factor ANOVA for repeated measures was computed
with the repeated measurement factors ‘substance’ (10 mg
escitalopram vs. placebo), ‘cue’ (no cue, doublecue,
centrecue and spatialcue) and ‘congruency’ (congruent,
incongruent and neutral trials) and an independent factor
‘sequence of intake’ which was included as participants
were assigned randomly to the starting substance (S1=first
escitalopram, then placebo vs. S2=first placebo, then
escitalopram). The factor ‘sequence’ is of special interest
as the randomization to the starting substance was not
fully counterbalanced. Furthermore, a new study (Verheij
et al. 2009) indicates differential effects of 5-HT on
measures of cognition in rats and therefore, we were also
interested in possible interactions of 5-HT and sequence as
this was never done in humans before. For the second
group (sub-chronic treatment), we conducted another
ANOVA with the same factors as above. For significant
effects, post-hoc comparisons were computed at α=0.05
and corrected for multiple comparisons (Bonferroni) by the
number of possible comparisons. Reported in the results
section are only those post-hoc tests relevant for our
analyses, but all possible comparisons were computed
automatically. Due to small and different sample sizes, we
also calculated standardised effect sizes according to Cohen
(1988). As effect size estimates are slightly biassed, they
are corrected using a factor provided by Hedges and Olkin
(1985).
In addition, we analysed plasma levels of escitalopram
from participants of the multiple-dose group before
starting the experiment on test days: participants reached
a mean plasma level of 6.9±4.1 ng/ml for escitalopram and a
mean plasma level for desmethylcitalopram of 5.5±2.2 ng/ml.
Plasma levels were determined about 24 h after the last
intake. Plasma levels of two participants were below
detection limit, and these participants were excluded
from further analysis. So, data of all 20 participants were
analysed for the acute treatment with nine participants for
S1 and 11 participants for S2. For the sub-chronic
treatment, data of 18 subjects were included, whereas nine
participants were analysed for S1 and another nine for S2.
All analyses were computed with Statistica 8.0.
Results
For the acute treatment group, we found an overall RT for
correct trials of 470 ms with placebo and 496 ms with
escitalopram for S1 which did not differ significantly from
each other (T=2.04, p=0.07) but showing a trend for
shorter reaction times with placebo. For S2, we found an
overall reaction time of 444 ms with escitalopram and
459 ms with placebo which differed significantly (T=−4.5,
p<0.01) indicating shorter reaction times with escitalo-
Psychopharmacology (2009) 207:213–223
pram. For the accuracy of responding we did neither find
differences between escitalopram and placebo for S1
(98.2% with placebo and 98.6% with escitalopram, T=
0.82, p=0.44) nor for S2 (97.2% with placebo and 98%
with escitalopram, T=1.06, p=0.31).
For the acute treatment, the ANOVA for repeated
measures revealed significant main effects of ‘cue’ (F=
64.7, p<0.01) and congruency (F=255.2, p<0.01). We did
neither find a significant main effect of ‘substance’ (F=1.2,
p>0.05) nor of ‘sequence of intake’ (F=1.6, p>0.05).
Furthermore, we found a significant interaction between
‘cue’ and ‘congruency’ (F=17.1, p<0.01) pointing out that
for all cueing conditions, the presence of incongruent
flankers increased RT, and however, this effect was enhanced
when subjects were given alerting cues (centre or double
cues) that contained no spatial information. Interestingly, we
also found a highly significant ‘substance x cue x sequence’
interaction (F=4.9, p<0.01) which is depicted in Fig. 3 (top
row). Post-hoc tests revealed for all cue conditions for S1
(first escitalopram, then placebo) significant differences
indicating shorter reaction times with placebo (pno cue <
0.01, ESno cue =0.24; pdouble cue <0.01, ESdouble cue =0.51;
pcentre cue <0.01, EScentre cue =0.55; pspatial cue <0.01, ESspatial
cue =0.43). Post-hoc tests for S2 (first placebo, then escita-
lopram) indicated shorter reaction times with escitalopram as
compared with placebo in all warning conditions except the
Fig. 3 Mean ANT reaction times of cue conditions (no, double, centre
and spatial cue) and their standard deviations (in millisecond) for the
acute treatment group. The top row shows reaction times for sequence
1 (S1 first escitalopram, then placebo) with escitalopram (black
squares) and placebo (black stars) on the left side and for sequence
2 (S2 first placebo, then escitalopram) with escitalopram (white
217
no-cue condition (pno cue =0.13, ESno cue =−0.17; pdouble cue <
0.01, ESdouble cue =−0.22; pcentre cue <0.01, EScentre cue =
−0.37; pspatial cue =0.02, ESspatial cue =−0.21) (Table 1).
Because training could also have an influence on attention
performance, reaction times for both sequences were plotted
separately for substances (Fig. 3, bottom row). It can be seen
that reaction times for all warning conditions were nearly the
same with placebo independent of sequence of intake (see
Fig. 4, bottom row on the right side), while reaction times
with escitalopram were differing. Calculated effect sizes for
escitalopram (ESno cue =0.66, ESdouble cue =0.76, EScentre cue =
0.88, ESspatial cue =0.67) indicated moderate to large effects
for differences in reaction times with escitalopram between
S1 and S2 and calculated effect sizes for placebo revealed
almost no effects in the warning conditions (ESno cue =0.38,
ESdouble cue =−0.14, EScentre cue =0.12, ESspatial cue =0.15)
between S1 and S2. To investigate possible effects on
training on placebo, we also calculated a multivariate
analysis of variance on placebo data with ‘sequence’ (S1
vs. S2) as independent factor and reaction times in cue
conditions as dependent variables. Results revealed no effect
on sequence for all cue conditions (Fno cue =0.83, pno cue >
0.05, Fdouble cue =0.1, pdouble cue >0.05, Fcentre cue =0.08,
pcentre cue >0.05, Fspatial cue =0.12, pspatial cue >0.05).
For the sub-chronic treatment group, we found an
overall reaction time for correct trials of 452 ms with
squares) and placebo (white circles) on the right side. On the bottom
row, the same reaction times are plotted separated for substances: on
the left side reaction times in cue conditions with escitalopram for S1
(black squares) and S2 (white squares) are shown and on the right
side, reaction times with placebo for S1 (black stars) and S2 (white
circles)
218 Psychopharmacology (2009) 207:213–223

Table 1 Means (M) and stan-

dard deviations (s.d.) of median Sequence ANT conditions Acute treatment Repeated treatment
reaction times (in millisecond)
of different ANT conditions Escitalopram Placebo Escitalopram Placebo
(cue: no, double, centre and
spatial; flanker: congruent, Cue Congruency M s.d. M s.d. M s.d. M s.d.
incongruent and neutral) with
escitalopram and placebo for S1 No Congruent 506 83 490 51 466 53 470 37
n=20 participants of the acute Incongruent 551 79 532 43 526 64 511 50
treatment group (with S1=
Neutral 500 74 487 44 467 40 467 34
sequence 1: first escitalopram,
then placebo of n=11; S2= S2 No Congruent 459 76 466 61 456 25 474 31
sequence 2: first placebo, then Incongruent 489 66 507 61 497 26 523 25
escitalopram of n=9) and for Neutral 460 62 470 60 460 27 474 27
n=18 participants of the repeat-
S1 Double Congruent 469 74 442 49 431 50 418 34
ed treatment group (with S1=
sequence1: first escitalopram, Incongruent 548 73 505 46 517 59 496 43
then placebo of n=9; S2= Neutral 471 70 444 49 431 43 426 45
sequence 2: first placebo, then S2 Double congruent 419 67 434 67 414 27 426 45
escitalopram of n=9)
incongruent 488 71 500 63 480 33 505 35
Neutral 415 67 434 61 416 32 428 39
S1 Centre Congruent 472 71 450 46 435 47 429 31
Incongruent 552 69 516 36 530 58 498 45
Neutral 476 60 444 39 439 57 427 34
S2 Centre Congruent 417 61 443 59 409 33 418 31
Incongruent 487 66 508 58 489 30 511 26
Neutral 419 65 440 53 411 25 428 35
S1 Spatial Congruent 452 69 424 38 420 46 410 37
Incongruent 503 81 484 48 487 68 467 54
Neutral 454 65 427 40 418 47 413 24
S2 Spatial Congruent 405 66 418 62 404 23 410 27
Incongruent 457 70 469 75 454 22 477 31
Neutral 404 63 419 59 402 26 411 35

placebo and 464 ms with escitalopram for S1 which did
not differ significantly from each other (T=−1.0, p=0.35).
For S2, we found an overall reaction time of 441 ms with
escitalopram and 457 ms with placebo which differed
significantly (T=−2.7, p<0.05) indicating shorter reaction
times with escitalopram. For the accuracy of responding,
we did neither find differences between escitalopram and
placebo for S1 (98.2% with placebo and 98.6% with
escitalopram, T=0.82, p=0.44) nor for S2 (97.2% with
placebo and 98% with escitalopram). We did not find
significant correlations between plasma escitalopram and
any behavioural measure.
The ANOVA for repeated measures for the sub-chronic
group revealed neither a significant main effect for
‘substance’ (F=0.2, p=0.6) nor for ‘sequence of intake’
(F=0.3, p=0.5). A significant main effect for ‘cue’ (F=
88.1, p<0.01) and ‘congruency’ (F=255.2, p<0.01) was
found. Furthermore, we found a significant interaction
between ‘cue’ and ‘congruency’ (F=15.6, p<0.01) as for
the acute treatment group and between ‘substance’ and
‘sequence of intake’ (F=7.7, p=0.014). The most interest-
ing interaction was found for ‘substance x sequence x
congruency’ (F=11.8, p<0.01) which is shown in Fig. 4.
Post-hoc tests revealed significant differences between
escitalopram and placebo for incongruent trials for S1
indicating shorter reaction times with placebo (pcongruent >
0.05, EScongruent =0.14; pincongruent <0.01, ESincongruent =0.37;
pneutral >0.05, ESneutral =0.15). For S2, we found significant
differences indicating shorter reaction times with escitalo-
pram for incongruent and neutral trials (pcongruent >0.05,
EScongruent =−0.38; pincongruent <0.01, ESincongruent =−0.91;
pneutral >0.05, ESneutral =−0.44). So, for the sub-chronic
treatment we found moderate to high effects for incongruent
trials indicating an influence of escitalopram on flanker task
that depends on sequence of intake (S1 vs. S2).
Additionally, to rule out possible training effects, we
calculated a multivariate analysis of variance on placebo
data with ‘sequence’ as independent factor and reaction
times in congruency conditions as dependent variables and
we found no significant effects of sequence on congruent
(F=0.001, p>0.05), incongruent (F=0.41, p>0.05) or
neutral trials (F=0.02, p>0.05) indicating that sequence
Psychopharmacology (2009) 207:213–223
Fig. 4 Mean reaction times of flanker conditions (congruent, incongruent and neutral) with escitalopram (black) and placebo (striped) separated
for sequence 1 (S1 first escitalopram, then placebo) and sequence 2 (S2 first placebo, then escitalopram) for the sub chronic treatment group
has no influence on reaction times with placebo. Here as
well, we calculated effect sizes for the comparison of S1
and S2 with escitalopram. Calculated effect sizes for
escitalopram (EScongruent =0.46, ESincongruent =0.72, ESneutral
=0.43) indicated moderate to large effects for differences in
reaction times with escitalopram between S1 and S2 and
calculated effect sizes for placebo revealed almost no effects
in the flanker conditions (EScongruent =0.00, ESincongruent =
0.27, ESneutral =0.07). So here again, for all congruency
conditions, we found differences between escitalopram and
placebo that depend on sequence of intake or the starting
substance, respectively.
In summary, reaction times with escitalopram differed
significantly from reaction times with placebo but depended
on sequence of intake and treatment duration: for the
participants who took a single dose of 10 mg escitalopram/
placebo reaction times in cue conditions with escitalopram
were significantly slower when escitalopram was taken first
and significantly faster, when placebo was taken first. And
for the sub-chronic treatment, we found significant slower
reaction times in incongruent trials with escitalopram when
taken escitalopram as first treatment and significant faster
reaction times in incongruent and neutral trials when
placebo was taken first.
Discussion
The present study was conducted to determine the influence
of serotonin on attention. We analysed two different
219
treatment groups, one group with a single dose of 10 mg
escitalopram and another group with multiple doses of
10 mg escitalopram.
For the acute treatment, we found a significant main
effect of ‘cue’, indicating shortest reaction times for trials
with spatial cues followed by reaction times in the double-
and centre-cue condition and the slowest reaction times
were found in the no-cue condition. Furthermore, we found
a significant main effect for congruency (flanker task),
indicating slower reaction times for incongruent trials than
for neutral or congruent trials. We found no significant
main effect for ‘substance’ or ‘sequence of intake’.
Additionally, we found a significant interaction between
‘cue x congruency’ indicating increased reaction times for
incongruent trials in the presence of alerting cues (double
cue and centre cue). So far, these results are in line with the
results from the original investigation of Fan et al. (2002).
But, the most interesting result for the acute treatment
group was the significant interaction between ‘substance x
cue x sequence of intake’. In the present study, participants
receiving an acute dose of 10 mg escitalopram and starting
their intake with escitalopram (S1) showed significantly
slower reaction times with escitalopram compared with
placebo in all cue conditions with no cue, double cue,
centre cue and spatial cue. This supports the results of
studies indicating a negative influence of 5-HT on attention
(Riedel et al. 2005). However, participants of the acute
treatment group starting with placebo (S2) had a significant
benefit in all cue conditions with escitalopram which is
consistent with the results from Nathan et al. (2000) who
220
found an improvement of attention after escitalopram in the
CFFT which is a measure for alertness, vigilance and
arousal. This benefit may be explained with a general
increase of central arousal as we also found an improve-
ment in overall reaction time. Arousal has been associated
with the 5-HT-system for a long time: Gray and Smith
(1969) and Gray (1982) postulated 5-HT having an indirect
influence on signal-to-noise ratio from gyrus dentatus to
subiculum which is an important structure for the encoding
of specific environmental information. These findings are
also supported by results of newer studies, as for example
from Abrams et al. (2005) who found a strong relationship
between 5-HT and arousal. Our results even indicate that 5-
HT not only plays an important role in the general concept
of arousal and tonic alertness but—as overall reaction times
may be understood as a measure of tonic alertness—in
attention, too. Furthermore, our results not only indicate the
role of 5-HT in attention, but this effect seems to be
moderated by sequence of the experimental condition. All
of our results concerning an acute treatment with escitalo-
pram were dependent on the starting substance—interest-
ingly, reaction times with placebo were nearly independent
of sequence of intake (see Fig. 3). One possible explanation
for these findings may be due to the fact that 5-HT may
interact with the level of familiarity or novelty of the
applied test: acute stimulation of 5-HT may interfere with
novel tasks while it benefits attentional processing with
familiar tasks. Ballaz et al. (2007) found a mediation of
attentional and memory processes in rats through 5-HT7
receptors and novelty-seeking behaviour which is thought
to model some aspects of sensation seeking in humans.
Even though escitalopram does not selectively propagate
serotonergic neurotransmission exclusively via the 5-HT7
receptor, this receptor subtype might play a critical role for
the interpretation of our results. This explanation is also in
line with the results of Verheij et al. (2009) who also found
hints for a possible interaction of 5-HT and novelty in rats
and supposed other 5-HT receptors (5-HT1A, 5-HT2 and 5-
HT3) to play an important role in this interaction.
The discussion on familiarity or novelty of tasks,
respectively, is a phenomenon which has been discussed
in the literature on memory performance. It seems probable
that 5-HT has a larger effect on learning than on attention.
This may be the case either via direct influence of 5-HT on
cortical or subcortical structures or via postsynaptic hetero-
ceptors that may regulate the function of several other
neurotransmitter systems (e.g. GABA; Stahl 2005; Mongeau
et al. 1997). Based on studies in rodents, the stimulation of
5-HT1A receptors generally produces learning impairments
by interfering with memory-encoding mechanisms (Yasuno
et al. 2004). In contrast, antagonists of 5-HT1A receptors
facilitate certain types of memory by enhancing hippocampal/
cortical cholinergic and/or glutamatergic neurotransmission
Psychopharmacology (2009) 207:213–223
(for a detailed review, see Ogren et al. 2008). Clarke et al.
(2005, 2007) even found differential effects of 5-HT
depletion in reversal learning but not in developing or
shifting an attentional set in several monkey studies. They
suggest a differential sensitivity of prefrontal regions (e.g.
ventrolateral prefrontal cortex) to 5-HT modulation, and
that the distribution of 5-HT and its receptors may exhibit
regional and laminar selectivity. Robbins (2007) and
Robbins and Roberts (2007) suggested the differential
effects of 5-HT on prefrontal functioning may reflect a
differential sensitivity of specific control processes to 5-HT
modulation. All in all, it seems quite likely that 5-HT is a
modulating neurotransmitter in adaptation processes and
that possible interactions have to be an important issue in
future research.
For the sub-chronic treatment group, we also found
significant differences depending on sequence of intake not
for warning conditions but for the flanker conditions. We
found significant slower reaction times in incongruent trials
with escitalopram as compared with placebo for partic-
ipants starting with escitalopram as first treatment (S1),
while participants who had escitalopram as second treat-
ment (S2) showed significant shorter reaction times in
incongruent and neutral trials. However, for the multiple-
doses group, we were not able to find differences in cue
conditions but in the flanker condition. As previously
mentioned, there may be an interaction with the familiarity
of the task and memory processes as we found a worsening
in reaction times with escitalopram for participants starting
with escitalopram and a benefit in reaction times with
escitalopram for participants starting with placebo.
In both cases (1 and 7 days intake), there might be an
effect of training, but this counter-argument is not
convincing as we calculated two multivariate analyses
of variance for the comparison of placebo data for the
acute and the repeated intake group and we did not find
any differences between S1 and S2. Additionally, we
calculated effect sizes for the comparisons between S1
and S2 separated for escitalopram and placebo. If there is
a pure effect of training, we should have found at least
moderate effect sizes for placebo, but we found small or
almost no differences in reaction times with placebo for
S1 and S2.
All in all, as we found interactions of substance with
sequence of intake in different conditions (cue vs. flanker)
it is possible that there may be an influence of serotonin on
attention which interacts with learning. Furthermore, it may
also be possible that the effect of serotonin on attention
manifests in different processing stages and depends on
treatment duration. So, it seems necessary to have a look at
what happens during cue and flanker processing. Posner
hypothesised the existence of three distinct networks
(alerting, orienting and conflict system) which are supposed
Psychopharmacology (2009) 207:213–223
to be independent from each other (Fernandez-Duque and
Posner 2001). Maybe one can speculate that escitalopram
as acute treatment acts on attention on early stages of
processing (cue processing) while as sub-chronic treatment,
it acts on later-processing stages (flanker). Cue processing
is hypothesised to work on brain structures like thalamus
and fronto-parietal areas, while flanker processing is related
to brain areas as anterior cingulum and fusiform gyrus (Fan
et al. 2005). So, it may be possible that a single oral dose of
10 mg escitalopram acts on more basal brain areas while a
multiple dose acts more on frontal areas.
One critical point to discuss is the difference in results
between single and repeated oral doses, even if results turn
to the same direction (interaction of substance x sequence).
But they also support the results of Robbins (2007) and
Robbins and Roberts (2007), suggesting a differential
sensitivity of control processes to 5-HT. First of all, one
can speculate that our results were due to a positive transfer
(training effect). Such a practise effect seems very unlikely
as we found significant interaction effects ‘substance x
sequence’ for the acute and the sub-chronic treatment. And
looking at the reaction times over all trials with placebo,
almost identical results are obtained for S1 and S2.
Finally, some limitations should be discussed. Method-
ological concerns come from the oral dosage of 10 mg and
7×10 mg/day, respectively. This dosage was tolerated well
by all of our participants while a higher dosage of 20 mg/
day escitalopram has been reported to be associated with
higher rates of adverse effects (Aronson and Delgado
2004). As we found only slight differences, one could
argue that the applied dosage was too low to influence
attention performance. We cannot rule out such a possibil-
ity, but wanted to reduce the risk of drop outs due to
adverse side effects. Wingen et al. (2007) used oral doses of
20 mg of escitalopram to enhance central 5-HT, but
nevertheless did not find any effect on vigilance.
Another methodological consideration concerns the
timing of testing that was conducted after a 200-min period
and was based on the pharmacokinetic profile of escitalo-
pram (to achieve coincidence of testing with approximated
time of plasma peak concentrations). According to Aronson
and Delgado (2004), the mean peak level following 20 mg
escitalopram occurs at 3± 1.5 h, while Burke (2002)
described maximal plasma concentrations of escitalopram
approximately 4 h after administration and Waugh and Goa
(2003) even stated maximal peak concentrations 4–5 h after
administration. Furthermore, citalopram plasma levels may
not necessarily correlate with the behavioural effects (Lader
et al. 1986).
Assuming results of the repeated dose group are an
artefact and based on the fact that subject did not take their
medication, we would have expected the results to be the
same as in the single-intake group. But it seemed unlikely
221
that the study participants had not taken their medication.
The serum concentrations measured in our sample were
similar to those observed by Klein et al. (2006). These
authors determined a serotonin reuptake transporter (SERT)
occupancy above 60% at serum concentrations of approxi-
mately 20 nmol/L after single escitalopram doses. Further-
more, Klein at al. (2006) in another publication demonstrated
that 6 h after the last of multiple 10 mg escitalopram doses,
the SERT occupancy was 82%, while it dropped to 63% 54 h
after the last dose (Klein et al. 2007). The serum concen-
trations of 21 nmol/L determined in our study in conjunction
with the SERT occupancy values reported by Klein et al.
(2006, 2007) for escitalopram doses of 10 mg indicate that
the SERT was occupied at least to a modest extent in most of
our subjects. Reis et al. (2007) reported highly variable
serum concentrations of 11 (min) to 111 (max) nmol/L for
escitalopram and 11 to 73 nmo/L for desmethylescitalopram
for a dose of 10 mg/day in 42 patients after 14 days of drug
intake. However, it cannot be ruled out that an intake of
7 days is too short for causing adaptive changes in synaptic
function and attain steady state. According to the aim of drug
compliance, our data seem to be quite reliable.
In summary, we found differential effects of escitalo-
pram and its ability to increase 5-HT levels in different
aspects of attention (cue and flanker processing) depending
on treatment duration and sequence of intake. A single oral
dose of 10 mg escitalopram increased reaction times in cue
conditions for participants starting with escitalopram as first
treatment, while for participants who got escitalopram as
second treatment we found a benefit in reaction times of
cue conditions as compared with placebo. For the sub-
chronic treatment group, we found similar results for
incongruent trials also depending on sequence of intake:
participants starting their intake with escitalopram had
significant slower reaction times in incongruent trials with
escitalopram as compared with placebo and significant
shorter reaction times when receiving escitalopram as
second treatment. Furthermore, we hypothesised these
differential effects of escitalopram on attention probably
to depend on the familiarity of testing materials: on the one
hand, there seems to be an inhibitory effect of increased
synaptic 5-HT concentrations for a new task (S1), while on
the other hand, an accelerating effect on performance could
be found for a familiar task (S2). But this phenomenon of
familiarity was found for different attention functions (cues
vs. flanker) and may interact with treatment duration (acute
vs. sub-chronic). The aspect of familiarity is especially
interesting because reaction times under placebo did not
differ from each other independent from sequence of intake.
Our results demonstrate a highly specific and dissociable
contribution of 5-HT in the modulation of attention processing.
The role of 5-HT in attention still remains not clear and further
investigations should seek to specify that role.
222
Acknowledgements This study was a research grant supported in
part by H. Lundbeck A/S (Copenhagen, Denmark). Lundbeck was not
responsible for the creation of the study, the choice of investigators,
the control of allocation schedule, the conduct of the trial, the
collection and monitoring of data, the analysis and interpretation and
the writing of the manuscript. B. Drueke, J. Baetz, M. Boecker and
Prof. Dr. S. Gauggel report no other conflicts of interest. Dr. O.
Moeller received travel support from Pfizer and Servier. Prof. Dr. C.
Hiemke has served as a consultant for Servier (Paris, France) and
Pfizer (New York, NY). He has served on the speakers’ bureau of
Bristol-Myers Squibb, Janssen Cilag, Otsuka, Pfizer, Astra Zeneca,
Sanofi-Aventis (Berlin, Germany), Lundbeck (Copenhagen,
Denmark), Servier and Eli Lilly (Indianapolis, IN). He has received
grant supports from Sanofi-Aventis and Pfizer. Prof. Dr. G. Gründer
has served as a consultant for Astra Zeneca (London, UK), Bristol-
Myers Squibb (New York, NY), Johnson & Johnson (Beerse,
Belgium), Otsuka (Rockville, MD) and Pfizer (New York, NY). He
has served on the speakers’ bureau of Astra Zeneca, Bristol-Myers
Squibb, Eli Lilly (Indianapolis, IN), Janssen Cilag, Otsuka, Pfizer,
Servier (Paris, France) and Wyeth (Madison, NJ). He has received
grant support from Alkermes (Cambridge, Ma), Bristol-Myers Squibb,
Eli Lilly, Johnson & Johnson, and Pfizer.
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