Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: A longitudinal study

Article (PDF Available)inPsychoneuroendocrinology 37(5):685-92 · September 2011with143 Reads
DOI: 10.1016/j.psyneuen.2011.08.012 · Source: PubMed
Abstract
We have previously reported that cognitive deficits are cross-sectionally associated with elevated cortisol in depressed patients. Here, we longitudinally examined if changes in cortisol secretion during treatment are associated with improvement of cognition. Cognitive function and salivary cortisol levels were longitudinally examined in 52 patients with major depression before and after 3 weeks of standardized selective serotonin reuptake inhibitor (SSRI) and an add-on treatment modulating the mineralocorticoid receptor and compared to a healthy control group (n=50) matched for age, gender and years of education. Across add-on treatment groups, SSRI treatment reduced salivary cortisol in patients to levels of healthy controls (time×group interaction p=.05). In patients, reduction of cortisol significantly correlated with improvement in depressive symptoms (r=.52, p<.01), speed of information processing (r=.50, p<.01), and cognitive set-shifting (r=.34, p=.03). Improved depressive symptoms were only associated with improved attention and working memory. Improvement of some cognitive domains during SSRI treatment was associated with decreasing cortisol secretion and was only to a lesser extent associated with improved depressive symptoms.

Figures

Changes
in
cortisol
secretion
during
antidepressive
treatment
and
cognitive
improvement
in
patients
with
major
depression:
A
longitudinal
study
Kim
Hinkelmann
*
,
Steffen
Moritz,
Johannes
Botzenhardt,
Christoph
Muhtz,
Klaus
Wiedemann,
Michael
Kellner,
Christian
Otte
Department
of
Psychiatry
and
Psychotherapy,
University
Medical
Center
Hamburg-Eppendorf,
Martinistrasse
52,
20246
Hamburg,
Germany
Received
24
May
2011;
received
in
revised
form
27
August
2011;
accepted
29
August
2011
1.
Introduction
Cognitive
deficits
are
characteristic
features
of
depression
and
increased
activity
of
the
hypothalamus—pituitary—adre-
nal
axis
(HPA)
leading
to
elevated
cortisol
is
often
reported
in
major
depression
(Belanoff
et
al.,
2001;
de
Kloet
et
al.,
2005a,b)
although
this
depends
on
type
and
severity
of
depression
as
well
as
on
sample
characteristics
(Stetler
Psychoneuroendocrinology
(2012)
37,
685—692
KEYWORDS
Cognitive
function;
HPA-axis;
Cortisol;
Depression;
Stress
Summary
Objectives:
We
have
previously
reported
that
cognitive
deficits
are
cross-sectionally
associated
with
elevated
cortisol
in
depressed
patients.
Here,
we
longitudinally
examined
if
changes
in
cortisol
secretion
during
treatment
are
associated
with
improvement
of
cognition.
Methods:
Cognitive
function
and
salivary
cortisol
levels
were
longitudinally
examined
in
52
patients
with
major
depression
before
and
after
3
weeks
of
standardized
selective
serotonin
reuptake
inhibitor
(SSRI)
and
an
add-on
treatment
modulating
the
mineralocorticoid
receptor
and
compared
to
a
healthy
control
group
(n
=
50)
matched
for
age,
gender
and
years
of
education.
Results:
Across
add-on
treatment
groups,
SSRI
treatment
reduced
salivary
cortisol
in
patients
to
levels
of
healthy
controls
(time
group
interaction
p
=
.05).
In
patients,
reduction
of
cortisol
significantly
correlated
with
improvement
in
depressive
symptoms
(r
=
.52,
p
<
.01),
speed
of
information
processing
(r
=
.50,
p
<
.01),
and
cognitive
set-shifting
(r
=
.34,
p
=
.03).
Improved
depressive
symptoms
were
only
associated
with
improved
attention
and
working
memory.
Conclusions:
Improvement
of
some
cognitive
domains
during
SSRI
treatment
was
associated
with
decreasing
cortisol
secretion
and
was
only
to
a
lesser
extent
associated
with
improved
depressive
symptoms.
#
2011
Elsevier
Ltd.
All
rights
reserved.
*
Corresponding
author.
Tel.:
+49
40
7410
54222;
fax:
+49
40
7410
53461.
E-mail
address:
hinkelma@uke.uni-hamburg.de
(K.
Hinkelmann).
Available
online
at
www.sciencedirect.com
j
our
na
l
h
omepa
g
e:
www.e
lse
vie
r.c
om/l
oca
te/
psyne
ue
n
0306-4530/$
see
front
matter
#
2011
Elsevier
Ltd.
All
rights
reserved.
doi:10.1016/j.psyneuen.2011.08.012
and
Miller,
2011;
Knorr
et
al.,
2010).
We
have
recently
shown
in
a
cross-sectional
study
that
cognitive
deficits
are
related
to
elevated
cortisol
in
depressed
patients
(Hinkelmann
et
al.,
2009)
and
several
studies
have
shown
a
normalization
of
HPA
axis
function
during
the
course
of
treatment
(McKay
and
Zakzanis,
2010).
However,
whether
HPA
normalization
is
related
to
improvement
of
cognitive
deficits,
is
still
under
debate.
To
our
knowledge,
only
two
studies
have
longitudinally
examined
the
association
between
HPA
normalization
and
improvement
of
cognition
in
depressed
patients
com-
pared
to
healthy
subjects:
O‘Brien
et
al.
(2004)
found
a
decrease
of
free
cortisol
in
older
depressed
patients
(mean
age
74
years)
during
treatment,
which
was
not
correlated
with
cognitive
improvement
(O‘Brien
et
al.,
2004).
Com-
pared
to
healthy
subjects,
patients
showed
only
slight
cognitive
improvement
and
about
half
of
them
fulfilled
formal
criteria
for
Mild
Cognitive
Impairment
(MCI)
during
follow-up.
Vythilingam
et
al.
(2004)
investigated
a
younger
and
medication
free
sample
of
depressed
patients
in
comparison
to
healthy
subjects.
During
SSRI
treatment,
patients
showed
a
decrease
of
cortisol
and
an
improvement
in
memory
func-
tion.
However,
at
baseline,
patients
did
not
exhibit
greater
cortisol
levels
compared
to
healthy
controls
and
cortisol
was
not
associated
with
cognition
before
treatment.
During
fol-
low-up
no
healthy
subjects
were
included
and
no
association
between
cognition
and
cortisol
was
found.
Tw o
further
studies
longitudinally
investigated
the
rela-
tionship
of
cortisol
and
cognition
in
depressed
patients
with-
out
including
a
healthy
control
group:
Zobel
et
al.
(2004)
demonstrated
an
association
of
the
decrease
in
cortisol
and
the
improvement
of
working
memory
function,
which
was
independent
of
symptom
severity.
In
contrast,
Reppermund
et
al.
(2007)
did
not
find
such
associations
but
reported
that
a
high
rate
of
depressed
inpatients
remained
cognitively
impaired
at
discharge.
In
summary,
the
few
existing
studies
regarding
HPA-axis
function
and
cognition
during
treatment
in
patients
with
major
depression
have
come
to
inconclusive
results
and
exhibit
several
limitations.
In
our
previous
cross-sectional
report
from
the
same
sample
(Hinkelmann
et
al.,
2009),
elevated
cortisol
was
specifically
associated
with
cognitive
deficits
in
verbal
and
non-verbal
memory
and
in
executive
function.
Here,
we
aimed
to
further
investigate
the
long-
itudinal
association
between
changes
of
HPA-axis
activity
and
cognition
in
depressed
patients
during
treatment.
We
hypothesized
that
decreases
in
cortisol
secretion
during
antidepressant
treatment
would
be
associated
with
improve-
ment
of
cognitive
function
in
the
same
domains,
i.e.
in
verbal
and
non-verbal
memory
and
in
executive
function.
2.
Methods
2.1.
Subjects
Clinical
and
demographic
characteristics
of
the
participants
are
shown
in
Table
1.
In
brief,
we
recruited
52
in-
and
outpatients
(15
men
and
37
women,
mean
age
35
11.5
years,
mean
years
of
education
11.3
1.6
years,
Hamilton
Rating
Scale
for
Depression
score
mean
27.2
4.5,
mean
number
of
episodes
1
1.2)
from
a
specialized
depression
clinic
at
the
Department
of
Psychiatry
and
Psychotherapy,
University
Medical
Center
Hamburg.
Inclusion
criteria
were
(1)
a
diagnosis
of
major
depressive
disorder,
single
or
recur-
rent
according
to
DSM-IV
criteria,
according
to
MINI-inter-
view
and
a
minimum
baseline
score
of
18
points
on
the
Table
1
Demographic
variables.
Patients
(N
=
52)
M
(SD)
Controls
(N
=
50)
M
(SD)
p
Age
35
(11.6)
35
(11.6)
n.s.
Male/female
15/37
15/35
n.s.
Education
(years)
11.3
(1.6)
11.5
(1.5)
n.s.
BMI
(SD)
24.3
(6.1)
23.2
(3.7)
n.s.
Smokers
50%
28%
.02
*
BDI
(SD)
30.9
(9.9)
3.3
(2.8)
<.01
*
Inpatients
654%
Non-psychotropic
concomitant
medication
N
=
6
N
=
5
Beta
blocker
2
Calcium
antangonists
1
Statins
2
Levothyroxine
3
Iodine
1
Warfarin
1
Non-steroidal
anti-inflammatory
medication
1
Escitalopram
dosage
(mean
mg/day
21)
**
13.2
(3.8)
n.a.
Lorazepam
dosage
(mean
mg/day
21)
0.18
(0.4)
n.a.
Zolpidem/Zopiclon
dosage
(mean
no.
tablets/day)
0.2
(0.5)
n.a.
Abbreviations:
BMI:
Body
Mass
Index,
BDI:
Beck
Depression
Inventory.
*
Based
on
independent
t-test
for
continuous
variables
and
chi-square
for
dichotomous
variables.
**
At
baseline
all
patients
were
free
of
psychotropic
medication
and
were
all
started
on
escitalopram
after
the
baseline
assessment.
686
K.
Hinkelmann
et
al.
Hamilton
Rating
Scale
for
Depression,
17-item
version
(HAMD-17);
(2)
age
from
18
to
65
years;
(3)
a
period
of
at
least
5
days
free
from
antidepressants,
antipsychotics,
mood
stabilizers,
and
other
medications
influencing
HPA
activity.
43%
of
the
patients
referred
were
first
episode
patients.
All
patients
were
referred
either
untreated
or
with
major
depression
despite
medication.
Only
7
patients
received
psychotropic
treatment
(except
benzodiazepines)
when
referred
to
the
clinic
and
needed
to
go
through
a
washed
out:
three
patients
took
mirtazapine,
1
trazodone,
1
parox-
etine,
1
escitalopram
and
1
buspirone.
Criteria
for
exclusion
were
(1)
dementia,
schizophrenia
spectrum
disorder,
bipolar
disorder,
substance
dependence
within
the
last
6
months
according
to
the
MINI-interview
(Sheehan
et
al.,
1998),
(2)
serious
medical
conditions,
espe-
cially
those
associated
with
adrenal
dysfunctions;
steroid
use
or
well
known
impact
on
HPA
activity
(e.g.
diabetes
mellitus)
or
cognitive
function,
(3)
pregnancy
and
nursing,
and
(4)
fluoxetine
medication
due
to
long
half
life
time.
A
control
group
of
50
healthy
subjects
(15
males
and
35
females)
recruited
by
public
postings
and
matched
for
age
(
3
years),
sex
and
years
of
education
(1
to
1
matching)
were
enrolled
in
the
study.
Subjects
were
free
of
former
and
present
DSM-IV
axis
I
disorders
according
to
the
MINI-inter-
view,
had
no
physical
illness
and
had
been
free
of
any
medication
at
least
3
months.
The
study
was
approved
by
the
local
ethics
committee.
After
complete
description
of
the
study
to
the
subjects,
written
informed
consent
was
obtained.
Cortisol
data
were
available
for
all
52
patients
and
50
controls
at
both
time
points.
Out
of
102
participants,
who
all
completed
day
1,
47
healthy
controls
and
44
patients
com-
pleted
both
days
of
the
neuropsychological
assessment.
2.2.
Design
and
procedure
All
participants
were
tested
twice:
at
baseline
(day
0)
and
after
3
weeks.
Prior
to
study
enrollment,
there
was
a
5-days
wash-out
period
for
those
patients
who
received
antidepres-
sive
medication
and
for
whom
we
decided
to
switch
anti-
depressive
medication
due
to
clinical
reasons
(no
patient
was
tapered
off
from
successful
medication
to
be
enrolled
into
the
study)
to
avoid
the
effects
of
antidepressant
discontinua-
tion
on
cortisol
secretion
(Michelson
et
al.,
2000).
After
the
wash-out
period,
all
patients
were
tested
without
antide-
pressant
during
the
baseline
testing.
After
the
baseline
assessment,
all
patients
started
treatment
with
escitalopram
10
mg
that
could
be
increased
to
15
or
20
mg
during
the
following
weeks.
Additionally,
as
this
study
was
part
of
a
randomized,
double-blind
controlled
trial
with
a
2:2:1
ran-
domization,
each
patient
received
an
add-on
treatment
for
3
weeks
modulating
the
mineralocorticoid
receptor
(19
patients
received
the
MR-agonist
fludrocortisone,
22
the
MR-antagonist
spironolactone
and
11
received
placebo
as
add-on
treatment)
as
described
in
(Otte
et
al.,
2010).
2.3.
Hormonal
assessment
Salivary
cortisol
was
collected
at
0800
h,
1200
h,
1600
h
and
2200
h
on
day
0
and
day
21.
All
participants
received
oral
and
written
instructions
on
the
correct
use
of
the
Salivette
salivary
collection
device
(Sarstedt,
Germany).
Participants
were
advised
not
to
eat,
drink,
smoke,
brush
their
teeth,
or
use
mouthwash
in
the
30
min
prior
to
salivary
collection.
Cortisol
was
determined
by
radioimmunoassay
(DRG,
Mar-
burg,
Germany).
Inter-
and
intraassays
coefficients
of
varia-
tion
were
below
8%.
Detection
limits
were
0.5
ng/ml
for
cortisol.
None
of
the
cortisol
values
were
below
the
detection
limit.
2.4.
Neuropsychological
assessment
Neuropsychological
tests
were
conducted
at
baseline
and
day
21
and
comprised
the
Auditory
Verbal
Learning
Test
(AVLT),
the
Digit
Span
Test,
Rey/Taylor
Figures,
letter
cancellation
test
(d2)
and
the
Trail
Making
Test
A
and
B
(TMT-A,
TMT-B).
All
neuropsychological
tests
were
administered
by
trained
psychologists.
The
time
of
testing
was
held
constant
between
1400
h
and
1600
h.
Auditory
verbal
learning
test
(AVLT)
(Lezak,
1995):
the
AVLT
is
a
measure
of
short-term
and
long-term
verbal
memory.
The
experimenter
reads
a
list
of
15
words
(list
A),
which
the
participant
is
requested
to
repeat
in
loose
order.
After
list
A
has
been
presented
five
times,
the
subject
is
asked
to
reproduce
words
from
a
newly
presented
list
(list
B).
Following
this,
the
subject
is
instructed
to
recall
the
words
from
list
A
without
renewed
presentation.
After
30
min,
the
subject
is
again
asked
to
repeat
the
words
from
list
A.
Outcome
measure
is
the
number
of
correctly
remem-
bered
words
after
each
presentation,
the
delayed
recall
after
30
min
for
long
term
memory
and
the
sum
of
all
presentations
(total
score).
Trail-making
test
(TMT)
(Reitan,
1992):
speed
of
cognitive
processing
was
assessed
with
the
TMT
part
A.
In
this
task,
the
subject
has
to
connect
encircled
numbers
in
ascending
order
as
quickly
as
possible.
Part
B
assesses
executive
function
and
requires
the
alternation
between
numbers
and
letters
in
ascending
order.
The
score
of
each
part
is
represented
by
the
time
needed
to
complete
the
task.
In
addition
to
direct
scores,
the
difference
score
(B—A)
reflects
switch
cost,
a
relatively
pure
indicator
of
executive
function
(Sanchez-
Cubillo
et
al.,
2009).
Forward
and
backward
digit
span
(Tewes,
1991):
this
task
forms
part
of
the
Wechsler
Adult
Intelligence
Scale
(WAIS).
During
the
forward
digit
span
task,
participants
are
asked
to
remember
a
series
of
digits
and
repeat
them
back
in
the
same
order.
During
the
backward
digit
span
task,
they
are
asked
to
repeat
the
digits
in
reverse
order,
which
taps
working
mem-
ory.
Outcome
measure
is
the
number
of
correctly
remem-
bered
digits.
Rey—Osterrieth
complex
figure
test
(RCFT)
and
Taylor
complex
figure
test
(TCFT)
(Osterrieth,
1944):
these
tests
measure
visuospatial
memory.
The
participant
is
first
required
to
copy
a
complex
figure.
Immediately
thereafter
and
20
min
later
the
figure
has
to
be
re-drawn
from
memory.
Outcome
measure
is
the
number
of
correctly
remembered
items
in
each
condition
(copy,
immediate
recall
and
delayed
recall).
To
adjust
for
baseline
performance
and
extract
a
true
memory
parameter,
we
adjusted
the
immediate
and
delayed
recall
by
the
performance
on
the
first
copy
trial
(‘‘baseline
correction’’).
Cortisol
and
cognition
in
the
course
of
MDD
687
Test
d2
(Brickenkamp,
1978):
The
Test
d2
is
a
letter
cancellation
test
that
taps
selective
attention/concentra-
tion.
In
this
task,
the
subject
is
instructed
to
cross
out
the
letter
d
whenever
it
is
accompanied
by
two
small
lines;
d’s
with
more
than
or
less
than
two
lines
or
any
stimuli
containing
the
character
p
serve
as
distracters.
Subsequent
to
a
practice
trial,
14
rows
with
target
and
distracter
stimuli
are
pre-
sented.
The
attention
score
is
the
number
of
correctly
identified
items.
2.5.
Statistical
analyses
The
cortisol
and
cognitive
measures
were
normally
distrib-
uted.
Mixed
analyses
of
covariance
(ANCOVA)
with
repeated
measures
design
were
conducted
to
investigate
differences
in
cortisol
levels
and
neuropsychological
tests
with
group
(patients
vs.
healthy
subjects)
as
between-subjects
factor
and
time
(day
0
vs.
day
21)
as
within-subjects
factor
adjust-
ing
for
potentially
confounding
variables.
For
cortisol
secre-
tion
during
the
day,
we
also
calculated
the
area
under
the
curve
with
respect
to
ground
(AUC)
as
described
in
(Pruessner
et
al.,
2003).
Differences
between
patients
and
controls
in
cortisol
AUC
for
day
0
and
day
21
were
then
analyzed
in
rm-
ANOVA.
To
investigate
the
effect
of
the
add-on
treatment
on
cognitive
measures
within
the
patient
group
mixed
analyses
of
variance
(ANCOVA),
adjusted
for
age
and
education,
with
repeated
measures
design
were
conducted
with
treatment
(spironolactone
vs.
fludrocortisone
vs.
placebo)
as
between-
subjects
factor
and
time
(day
0
vs.
day
21)
as
within-subjects
factor.
Pearson
correlation
coefficients
were
determined
in
the
total
sample
and
in
each
group
separately
to
examine
the
association
between
the
change
of
cortisol
secretion
and
change
in
cognitive
function.
In
order
to
control
for
poten-
tially
confounding
variables,
we
also
conducted
linear
regres-
sion
analyses
for
neuropsychological
tests.
A
sample
size
of
n
=
52
is
sufficient
to
detect
the
effect
size
of
f2
=
0.25
(medium
effect
size)
with
80%
power
in
linear
regression
analyses
with
four
predictors.
We
adjusted
all
analyses
comparing
patients
with
controls
for
smoking
because
depressed
patients
were
more
likely
to
smoke
as
described
previously
(Hinkelmann
et
al.,
2009).
In
all
analyses,
two-sided
tests
were
used
and
as
nominal
level
of
significance,
a
=
0.05
was
accepted
while
a
0.10
was
considered
a
trend.
3.
Results
3.1.
Cortisol
secretion
Three
weeks
of
antidepressant
treatment
reduced
salivary
cortisol
in
patients
to
levels
of
age-
and
sex
matched
healthy
subjects
(repeated-measures
ANCOVA,
adjusted
for
smoking,
time
group
interaction
F(1;99)
=
3.8,
p
=
.05,
partial
Eta
squared
=
.04)
(see
Fig.
1).
3.2.
Cognitive
function
As
indicated
in
Table
2,
both
patients
and
healthy
controls
improved
in
most
cognitive
variables
over
time.
However,
patients
improved
to
a
greater
extent
in
verbal
memory
(repeated-measures
ANCOVA,
adjusted
for
smoking,
group
-
time
interaction,
AVLT
long
term
memory:
F(1;90)
=
5.1,
p
=
.02,
partial
Eta
squared
=
.06)
and
non-verbal
memory
(repeated-measures
ANOVA
group
time
interaction,
Rey/
Taylor
Figure:
F(1;90)
=
8.8,
p
<
.01,
partial
Eta
squared
=
.09)
compared
to
healthy
controls.
In
fact,
after
three
weeks
patients
still
performed
worse
compared
to
healthy
controls
(ANCOVA,
adjusted
for
smok-
ing,
significant
for
Digit
Span
Forward:
F(1;90)
=
5.0,
p
=
.02,
partial
Eta
squared
=
.05;
Rey/Taylor;
F(1;90)
=
26.1,
p
<
.01,
partial
Eta
squared
=
.23
and
d2:
F(1;90)
=
8.9,
p
<
.01,
partial
Eta
squared
=
.09)
in
comparison
to
healthy
subjects
(see
Table
2)
indicating
ongoing
relative
cognitive
deficits
in
patients
compared
to
controls
in
these
domains.
Repeated-measures
ANCOVA
(adjusted
for
age
and
educa-
tion)
revealed
no
differences
between
the
three
treatment
groups
over
time
(repeated-measures
ANCOVA,
p
>
.05
for
all
time
(baseline
vs.
day
21)
treatment
(fludrocortisone
vs.
spironolactone
vs.
placebo)
interactions).
3.3.
Cortisol
secretion
and
cognitive
function
In
patients,
reduction
of
cortisol
was
significantly
associated
with
improved
cognitive
function
in
TMT-A
(r
=
.50,
p
<
.01)
and
TMT-B
(r
=
.34,
p
=
.03).
Noteworthy,
reduction
of
corti-
sol
showed
a
trend
towards
an
association
with
AVLT
total
score
(r
=
.26,
p
=
.09),
TMT-Difference
Score
(B—A)
(r
=
.25,
p
=
.10),
Rey/Taylor
Figure
copy
(r
=
.28,
p
=
.07),
and
Digit
Span
Backward
(r
=
.27,
p
=
.08)
(see
Table
3).
As
indicated
in
Table
3,
the
correlations
in
the
total
sample
were
driven
by
the
depressed
patients.
The
add-on
treatment
had
no
effect
on
the
cognitive
measures.
However,
to
control
for
any
residual
confounding
and
to
further
control
for
other
potentially
confounding
Figure
1
Salivary
cortisol
(area
under
the
curve)
of
patients
(n
=
52)
before
and
after
a
3-weeks
treatment
with
escitalopram
compared
to
healthy
subjects
(n
=
50).
Bars
represent
mean
area
under
the
curve
(AUC)
cortisol
values.
Repeated-measures
ANCOVA
revealed
a
significant
time
group
interaction
(
p
=
.05).
Post
hoc
tests
revealed
a
significant
reduction
of
cortisol
in
patients
(t-test,
t
=
2.5,
df
=
51,
p
=
0.01).
688
K.
Hinkelmann
et
al.
variables,
linear
regression
analyses
for
each
cognitive
test
as
outcome
variable
and
with
age,
sex
and
add-on
treatment
as
predictor
variables
were
conducted
for
the
patient
group.
Adjusting
for
age,
sex
and
add-on
treatment,
delta
AUC
Cortisol
was
significantly
associated
with
TMT-A
and
Rey/
Taylor
copy
(
p
<
.05)
and
on
trend
level
with
AVLT
total
score,
TMT-B,
d2,
Rey/Taylor
immediate
and
delayed
recall
(all
p-values
<
10).
3.4.
Psychopathology
Three
weeks
of
antidepressant
treatment
significantly
improved
depression
(HAMD
day
0
=
mean
27.2
SD
4.5
vs.
day
21
15.2
SD
7.3,
paired
t-test,
p
<
.01,
effect
size
r
=
.71).
Importantly,
improvement
of
psychopathology
was
strongly
correlated
with
decreases
in
cortisol
(r
=
52,
p
<
01)
(see
Fig.
2),
but
only
moderately
correlated
with
cognitive
improvement
(significant
only
for
the
letter
cancellation
test
(r
=
.35,
p
=
.02)
and
digit
span
backward
(r
=
.33,
p
=
.03).
4.
Discussion
In
this
study,
we
longitudinally
examined
if
reduction
of
cortisol
is
associated
with
improvement
of
cognitive
function
in
the
course
of
treatment
of
depressed
patients.
We
found
that
antidepressant
treatment
reduced
salivary
cortisol
in
depressed
patients
to
the
level
of
healthy
subjects
within
three
weeks.
The
reduction
of
cortisol
was
related
to
improvement
of
some
but
not
all
cognitive
domains.
Sec-
ondly,
the
reduction
of
cortisol
was
correlated
with
improve-
ment
of
psychopathology.
However,
cognitive
improvement
was
not
accounted
for
by
psychopathological
improvement.
Table
3
Correlation
analysis
of
change
scores
in
salivary
cortisol
and
neuropsychological
tests.
Both
groups
(n
=
91)
Patients
(n
=
44)
Healthy
subjects
(n
=
47)
Cognitive
domain
(test)
D
AUC
cortisol
r,
(
p)
D
AUC
cortisol
r,
(
p)
D
AUC
cortisol
r,
(
p)
Verbal
memory
D
AVLT
total
Score
0.11
(0.31)
0.26
(0.09)
**
0.05
(0.73)
D
AVLT
delayed
recall
0.12
(0.26)
0.19
(0.22)
0.13
(0.39)
D
TMT-A
0.29
(<0.01)
*
0.50
(<
0.01)
*
0.08
(0.56)
D
TMT-B
0.32
(<0.01)
*
0.34
(0.03)
*
0.28
(0.06)
**
D
TMT-diff
(B—A)
0.25
(0.02)
*
0.25
(0.10)
**
0.20
(0.17)
D
Digit
span
forward
0.06
(0.57)
0.02
(0.89)
0.11
(0.47)
D
Digit
span
backward
0.07
(0.53)
0.27
(0.08)
**
0.22
(0.15)
D
Rey/Taylor
copy
0.24
(0.03)
*
0.28
(0.07)
**
0.08
(0.64)
D
Rey/Taylor
immediate
recall
(baseline
corrected)
0.10
(0.35)
0.20
(0.21)
0.08
(0.58)
D
Rey/Taylor
delayed
recall
(baseline
corrected)
0.09
(0.39)
0.13
(0.39)
0.11
(0.48)
D
d2_concentration
score
0.19
(0.08)
**
0.25
(0.10)
0.09
(0.54)
AUC
=
area
under
the
curve,
p
=
probability.
*
p
<
0.05.
**
p
<
0.1.
Table
2
Mean
scores
(SE)
of
cognitive
variables
for
patients
before
and
after
treatment
compared
to
healthy
subjects.
Patients
(n
=
44)
Healthy
subjects
(n
=
47)
Cognitive
domain
Day
0
Day
21
Day
0
Day
21
(Test)
Mean
(SD)
Mean
(SD)
Mean
(SD)
Mean
(SD)
AVLT
Total
score
81.4
(15.6)
82.1
(16.0)
86.8
(12.2)
85.6
(11.4)
Delayed
recall
11.8
(2.8)
12.0
(3.2)
13.2
(1.9)
12.5
(2.7)
TMT-A
(time)
26.1
(7.8)
22.6
(7.1)
26.6
(9.8)
23.7
(8.3)
TMT-B
(time)
70.8
(40.2)
57.2
(32.9)
61.3
(22.6)
54.5
(18.9)
TMT-diff
(time)
44.7
(34.6)
34.6
(24.7)
34.7
(19.0)
30.8
(16.1)
Digit
span
forward
8.3
(2.5)
8.8
(2.7)
9.6
(2.1)
9.9
(2.5)
Digit
span
backward
7.2
(2.3)
7.3
(2.7)
7.4
(2.5)
7.6
(2.6)
Rey/Taylor
copy
29.3
(4.2)
30.0
(4.0)
35.5
(1.1)
35.5
(1.2)
Rey/Taylor
immediate
recall
18.1
(7.9)
23.2
(6.9)
24.5
(5.4)
26.7
(4.6)
Rey/Taylor
delayed
recall
17.5
(7.7)
21.6
(5.8)
24.6
(5.6)
26.7
(4.4)
d2
Concentration
score
158.3
(38.9)
185
(52.1)
190.7
(38.4)
215.4
(45.2)
Patients
improved
to
a
greater
extent
in
verbal
memory
(repeated-measures
ANCOVA
group
time
interaction,
AVLT
long
term
memory:
F(1;90)
=
5.1,
p
=
.02)
and
non-verbal
memory
(repeated-measures
ANCOVA
group
time
interaction,
Rey/Taylor
Figure:
F(1;90)
=
8.8,
p
<
.01)
compared
to
healthy
controls.
AVLT:
Auditory
Verbal
Learning
Test,
TMT
A
and
B:
Trail
Making
Test
A
and
B.
Cortisol
and
cognition
in
the
course
of
MDD
689
It
has
long
been
hypothesized
that
increased
cortisol
secretion
might
be
responsible
for
cognitive
deficits
in
depressed
patients
(Belanoff
et
al.,
2001;
de
Kloet
et
al.,
2005a).
However,
to
the
best
of
our
knowledge,
this
is
the
first
study
demonstrating
the
association
of
HPA
normaliza-
tion
with
cognitive
improvement
in
some
but
not
all
domains
in
depressed
patients
compared
to
healthy
controls.
Our
results
suggest
that
lowering
cortisol
or
blocking
its
effects
might
be
a
promising
approach
in
the
future
treatment
of
patients
with
major
depression.
Our
results
are
in
line
with
Zobel
et
al.
(2004)
who
found
cortisol
reduction
during
antidepressant
treatment
to
be
correlated
with
improvement
in
cognitive
function
in
patients
with
major
depression.
However,
whereas
Zobel
et
al.
found
an
association
with
working
memory,
in
our
study
cortisol
reduction
was
significantly
associated
only
with
executive
function,
while
verbal
and
non-verbal
memory
were
suggestive
of
an
association,
but
did
not
reach
statis-
tical
significance.
The
few
existing
other
prospective
studies
have
come
to
results
challenging
the
theory
of
a
causal
role
of
cortisol
regarding
cognitive
deficits
(Reppermund
et
al.,
2007;
O‘Brien
et
al.,
2004;
Vythilingam
et
al.,
2004)
but
these
studies
differed
in
some
aspects
from
our
study.
In
some
studies,
patients
were
already
on
medication
during
the
baseline
assessment
(Reppermund
et
al.,
2007;
O‘Brien
et
al.,
2004).
Other
studies
did
not
include
a
healthy
control
group
(Repper-
mund
et
al.,
2007),
did
focus
on
elderly
patients
only
that
were
to
great
extent
cognitively
impaired
independent
from
depres-
sion
(O‘Brien
et
al.,
2004),
or
patients
did
not
show
elevated
cortisol
compared
to
healthy
controls
(Vythilingam
et
al.,
2004).
Thus,
future
studies
should
examine
to
what
extent
medication,
in-
and
exclusion
criteria
or
gender
aspects
mod-
erate
the
longitudinal
association
between
cortisol
secretion
and
cognitive
function
in
depressed
patients.
Our
results
suggest
that
the
improvement
of
cognitive
function
after
restoring
the
HPA
axis
is
not
specific
for
a
single
cognitive
function
since
more
cognitive
domains
improved.
The
strongest
correlation
with
cortisol
reduction
in
our
sample
was
with
speed
of
information
processing
(TMT-A)
and
executive
function
(TMT-B),
whereas
memory
functions
were
only
related
on
trend
level.
The
TMT-A,
a
test
demand-
ing
visual
search
abilities
(Sanchez-Cubillo
et
al.,
2009),
has
been
linked
to
frontal
lobe
impairment
(Demakis,
2004),
but
also
exhibits
intercorrelations
with
working
memory
func-
tions
(Sanchez-Cubillo
et
al.,
2009).
In
our
study,
the
decrease
of
cortisol
was
correlated
with
improvement
in
cognition
and
improvement
in
psychopathol-
ogy.
The
latter
two,
however,
were
only
moderately
asso-
ciated
with
each
other.
This
suggests
that
improvement
of
cognition
is
not
just
a
function
of
improvement
in
psycho-
pathology
which
is
in
line
with
Zobel
et
al.
(2004)
but
in
contrast
to
Reppermund
et
al.
(2007),
who
found
the
improvement
of
psychopathology
to
be
related
with
speed
of
information
processing.
Although
our
results
indicate
that
cortisol
secretion
is
associated
with
changes
in
cognitive
function
above
and
beyond
improved
psychopathology,
future
longitudinal
studies
with
repeated
assessments
and
a
more
extended
observation
period
are
needed
to
disen-
tangle
the
temporal
associations
among
changes
in
cortisol,
cognition,
and
psychopathology
during
treatment.
In
our
study,
participants
improved
across
groups
in
cog-
nitive
variables
indicating
a
learning
effect.
We
therefore
conclude
that
it
will
be
important
to
include
healthy
control
groups
in
order
to
control
for
this
effect
in
future
studies.
Interestingly,
compared
to
healthy
subjects
patients
improved
significantly
stronger
in
verbal
and
non-verbal
memory
functions,
which
are
hippocampus
related
domains.
These
results
are
consistent
with
the
hypothesis
that
ele-
vated
cortisol
exerts
detrimental
effects
on
the
hippocampus
(de
Kloet
et
al.,
2005b),
the
brain
region
of
highest
gluco-
corticoid
and
mineralocorticoid
receptor
density.
However,
it
should
be
kept
in
mind
that
after
three
weeks
of
treatment
patients
still
fared
worse
in
the
Digit
Span
forward
test
(working
memory)
and
the
Rey/Taylor
Figure
(non-verbal
memory),
which
is
in
line
with
Douglas
et
al.
(2011).
Our
results
are
also
consistent
with
other
data
supporting
a
fundamental
role
of
elevated
cortisol
in
cognitive
deficits:
acute
and
chronic
glucocorticoid
treatment
leads
to
cogni-
tive
impairments
in
healthy
subjects
(Kirschbaum
et
al.,
1996;
Lupien
and
McEwen,
1997;
Young
et
al.,
1999;
New-
comer
et
al.,
1999)
as
well
as
to
impaired
cognitive
function
in
patients
on
long-term
prescription
corticosteroid
therapy
(Brown
et
al.,
2004).
Patients
with
glucocorticoid
excess
due
to
Cushing’s
disease
exhibit
worse
cognitive
function
(Forget
et
al.,
2000;
Starkman
et
al.,
2001)
and
improve
after
successful
treatment
(Starkman
et
al.,
2003;
Hook
et
al.,
2007).
And
lastly,
spatial
working
memory,
verbal
fluency,
and
spatial
recognition
memory
improved
in
depressed
bipo-
lar
patients
after
blocking
the
glucocorticoid
receptor
(Young
et
al.,
2004).
Our
study
had
several
strengths.
We
examined
‘real-
world’’,
treatment-seeking
patients
with
moderate
to
severe
depression
and
all
patients
were
studied
at
baseline
not
on
psychotropic
medication
for
at
least
five
days.
However,
several
limitations
must
also
be
acknowledged:
our
correla-
tional
statistical
methods
do
not
allow
definite
inferences
about
causality.
Only
two
cognitive
variables
were
signifi-
cantly
correlated
with
the
decrease
of
cortisol,
whereas
five
cognitive
variables
were
suggestive
of
an
association,
but
did
not
reach
statistical
significance.
Therefore,
we
were
only
partially
able
to
confirm
our
hypothesis.
However,
p-values
Figure
2
Correlation
between
changes
in
salivary
cortisol
and
Hamilton
Depression
Rating
Scale
in
patients.
Pearson
correla-
tion:
r
=
0.52,
p
<
0.01,
AUC
=
area
under
the
curve
for
cortisol.
690
K.
Hinkelmann
et
al.
depend
on
effects
sizes
and
sample
size.
For
example,
in
our
study,
an
r-value
of
0.25
is
significant
in
the
total
sample,
whereas
the
same
r-value
is
a
weak
trend
in
the
depressed
group
due
to
smaller
sample
size.
For
the
delta
of
Rey/Taylor
copy,
the
r-value
is
0.24
in
the
total
group
and
significant
but
0.28
in
the
depressed
group
and
non-significant.
There
are
more
examples
like
these
in
our
study
(see
Table
3).
We
think
it
would
be
unfortunate
to
interpret
an
r-value
of
0.24
in
the
total
group
(because
it
is
significant)
but
not
to
interpret
an
r-
value
of
0.28
(because
it
is
non-significant).
However,
due
to
multiple
comparisons
the
conclusions
that
can
be
drawn
are
limited.
Secondly,
patients
were
treated
with
an
add-on
medica-
tion
modulating
the
mineralocorticoid
receptor
during
the
first
three
weeks
of
treatment
as
described
in
Otte
et
al.
(2010),
which
might
have
an
impact
on
cognitive
function.
However,
this
was
not
the
case
in
this
study.
We
nevertheless
considered
the
add-on
treatment
as
a
covariate
in
regression
analyses
to
avoid
any
residual
confounding.
Furthermore,
if
anything,
the
‘noise’
we
hereby
induced
in
the
association
between
changes
in
cortisol
secretion
and
improvement
in
cognitive
function
HPA-axis
function
would
have
biased
our
results
towards
the
null
hypothesis.
Furthermore,
alterations
in
executive
function
are
com-
mon
in
depressed
patients
and
we
used
only
one
measure
(TMT-B)
to
specifically
examine
executive
function.
Three
weeks
of
follow-up
are
a
relatively
short
period
of
time
to
assess
changes
in
cognitive
function
in
depressed
patients
some
of
whom
were
still
not
in
remission.
However,
in
this
time
span
salivary
cortisol
was
significantly
reduced
to
the
level
of
healthy
subjects
and
effects
in
cognition
could
be
seen,
as
in
other
studies
with
short
observation
periods
(Zobel
et
al.,
2004).
Nevertheless,
this
study
was
not
designed
to
assess
the
question
if
cognitive
deficits
are
state
or
trait
related
in
MDD.
Therefore,
further
studies
should
systemati-
cally
explore
the
effects
of
treatment-resistance,
response,
and
remission
on
changes
in
cognitive
function
in
depressed
patients
over
a
longer
period
of
time.
Finally,
we
did
not
investigate
the
cortisol
awakening
response
(Fries
et
al.,
2009).
Differences
in
cortisol
level
between
patients
and
healthy
subjects
as
well
as
correlations
might
have
been
even
more
pronounced
using
this
measure
(Vreeburg
et
al.,
2009).
In
summary,
our
results
demonstrate
that
the
normal-
ization
of
the
HPA
axis
activity
is
associated
with
the
improve-
ment
of
cognition
in
patients
with
major
depression
during
antidepressant
treatment.
HPA
activity
might
therefore
be
a
promising
target
to
treat
cognitive
dysfunction
in
major
depression.
Contributors
KH
and
CO
designed
the
study,
wrote
the
protocol
and
the
manuscript.
JB,
KH
and
CM
examined
the
subjects
and
collected
the
data.
MK,
KW
and
SM
helped
to
manage
the
analyses
and
to
interpret
the
data.
Role
of
funding
source
This
work
was
supported
by
the
German
Research
Foundation
(Deutsche
Forschungsgemeinschaft,
grant
OT
209/3-1,
3-2).
The
German
Research
Foundation
had
no
role
in
the
collection
of
data,
interpretation
of
results,
or
preparation
of
this
manu-
script.
We
have
no
conflict
of
interest.
Conflict
of
interest
Dr.
Wiedemann
served
as
a
consultant
to,
or
has
been
on
the
speakers
boards
of
AstraZeneca,
BristolMyersSquibb,
Jans-
sen,
Pzer,
Servier
and
Wyeth.
Dr.
Kellner
received
funding
for
investigator
initiated
trials
by
Lundbeck
and
Pzer.
He
is
a
member
of
an
advisory
board
for
Wyeth.
Dr.
Otte
is
on
the
speaker’s
board
of
Astra
Zeneca,
Lundbeck
and
Servier.
Dr.
Hinkelmann,
Dr.
Moritz,
Dr.
Muhtz
and
Dr.
Botzenhardt
report
no
conflict
of
interest.
Acknowledgements
We
are
grateful
to
the
excellent
technical
assistance
of
Iris
Remmlinger-Marten
and
Kirsten
Huwald.
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692
K.
Hinkelmann
et
al.
    • "Einer Placebo-Kontrollgruppe bedienten sich bislang, abgesehen von einer kleinen Studie, in der Reboxetin (nicht jedoch Paroxetin) günstige Effekte auf die kognitive Funktionsfähigkeit bei depressiven Patienten gezeigt hat [14], ausschließlich die beiden oben beschriebenen Studien, in denen Vortioxetin verglichen mit Placebo günstige Effekte zeigte [31, 36]. Unklar bleibt, ob Studien, die in einem Test-Retest-Design eine gesunde Kontrollgruppe beinhalteten , zeigen für verschiedene Antidepressiva (Escitalopram, Sertralin, Fluoxetin, Duloxetin) eine gewisse Verbesserung der Kognition depressiver Patienten, die jedoch nicht das Niveau gesunder Kontrollprobanden erreichten [19, 21]. In den meisten Studien wurde jedoch die zweite Testung bereits wenige Wochen nach Behandlungsbeginn durchgeführt, sodass möglicherweise Herrera-Guzman [20] 2008 n = 20 MD* Bupropion (150 mg/Tag) Patienten verbesserten sich im visuellen Gedächtnis und in der Verarbeitungsgeschwindigkeit. "
    [Show abstract] [Hide abstract] ABSTRACT: Due to its high life-time prevalence, major depression is one of the most urging medical problems in public health care. In many depressed patients cognitive dysfunction is present not only during the depressive episode but also as a residual symptom after remission has been achieved. Residual symptoms like cognitive dysfunction impair the patients' social functional level as well as their quality of life and they increase the risk of relapse. Up to now, only few studies have specifically examined the effects of antidepressants on cognitive dysfunction in depressed patients. Vortioxetine is a multimodal antidepressant acting on serotonin (5-HT) receptors in several ways: as an antagonist on 5-HT3, 5-HT7, and 5-HT1D receptors, as a partial agonist on 5-HT1B receptors, and as an agonist on 5-HT1A receptors; furthermore, it inhibits the 5-HT transporter. In preclinical animal studies, vortioxetine showed positive effects on learning and memory. The effects of vortioxetine on cognitive dysfunction in depressed patients are discussed in the context of available studies with other antidepressants. © 2015, Wissenschaftliche Verlagsgesellschaft MBH. All rights reserved.
    Full-text · Article · Jan 2015 · Psychoneuroendocrinology
    • "Saliva has been used to test for cortisol levels as an indicator of chronic stress in healthy patients [83]. Elevated salivary cortisol levels have been identified in depressed patients [84, 85]. Nevertheless, cortisol levels in saliva can suggest other, non-mental health conditions as well, and while its noninvasive nature and ease of collection make salivary diagnostics extremely attractive, much work remains to be done before an effective and reliable screening tool using saliva is available [86]. "
    [Show abstract] [Hide abstract] ABSTRACT: Major depressive disorder (MDD) affects approximately 14.8 million adults in the United States, which is about 6.7 % of the US population. MDD impacts most activities of daily living, including oral hygiene practices and use of dental resources. This review article provides information related to underlying mechanisms of disease, diagnosis, and treatment so that dentists may best address patients’ dental concerns in the context of underlying depression. Laboratory and psychological screening tools are also discussed in relation to specific practice recommendations for managing patients with MDD as well as identifying patients with underlying symptoms who may be at risk for MDD.
    Article · Sep 2014
    • "In particular, the classical " glucocorticoid cascade hypothesis " postulated that chronic stress-related increases in cortisol levels would lead to hippocampal neurotoxic damage and progressive disinhibition of the HPA axis in a feed-forward cycle (Sapolsky et al., 1986 ). Consistent with this, heightened cortisol levels predicted persisting hippocampalrelated cognitive deficits both in younger adults with MDD (Hinkelmann et al., 2012) and in older, non clinically depressed individuals (Lupien et al., 2005; Beluche et al., 2010; Comijs et al., 2010). Instead, in apparent contrast with this hypothesis, two of the studies we included in the metaanalysis assessed the performance in various neuropsychological domains: deficits in memory and "
    [Show abstract] [Hide abstract] ABSTRACT: axis and aging in depression: systematic review and meta-analysis, Psychoneuroendocrinology (2013), http://dx.doi.org/10.1016/j.psyneuen.2013.12.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
    Full-text · Article · Dec 2013
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